PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of ijmsMDPIhomeThis articleThis journalInstructions for authorsSubscribeIJMS
 
Int J Mol Sci. 2016 June; 17(6): 990.
Published online 2016 June 22. doi:  10.3390/ijms17060990
PMCID: PMC4926518

DNA Damage and Pulmonary Hypertension

Guillermo T. Sáez, Academic Editor

Abstract

Pulmonary hypertension (PH) is defined by a mean pulmonary arterial pressure over 25 mmHg at rest and is diagnosed by right heart catheterization. Among the different groups of PH, pulmonary arterial hypertension (PAH) is characterized by a progressive obstruction of distal pulmonary arteries, related to endothelial cell dysfunction and vascular cell proliferation, which leads to an increased pulmonary vascular resistance, right ventricular hypertrophy, and right heart failure. Although the primary trigger of PAH remains unknown, oxidative stress and inflammation have been shown to play a key role in the development and progression of vascular remodeling. These factors are known to increase DNA damage that might favor the emergence of the proliferative and apoptosis-resistant phenotype observed in PAH vascular cells. High levels of DNA damage were reported to occur in PAH lungs and remodeled arteries as well as in animal models of PH. Moreover, recent studies have demonstrated that impaired DNA-response mechanisms may lead to an increased mutagen sensitivity in PAH patients. Finally, PAH was linked with decreased breast cancer 1 protein (BRCA1) and DNA topoisomerase 2-binding protein 1 (TopBP1) expression, both involved in maintaining genome integrity. This review aims to provide an overview of recent evidence of DNA damage and DNA repair deficiency and their implication in PAH pathogenesis.

Keywords: DNA damage, DNA-damage response, pulmonary hypertension, inflammation, oxidative stress

1. Introduction

Pulmonary hypertension (PH) is defined by a mean pulmonary arterial pressure over 25 mmHg at rest and is diagnosed by right heart catheterization. Different groups are defined based on PH etiology. In its most common forms, PH can be due to chronic thromboembolic clots (Group 4), consecutive to left-sided heart or lung diseases (Group 2 and 3 respectively), or due to primary arterial defects (Group 1, called pulmonary arterial hypertension [PAH]) [1,2]. PAH is characterized by a progressive obstruction of distal pulmonary arteries and formation of plexiform lesions leading sooner or later to heart failure. The pathogenesis of PAH is complex and involves pulmonary arterial endothelial cells (PAECs) dysfunction, pulmonary arterial smooth muscle cells (PASMCs) proliferation, apoptosis resistance, metabolic shift (Warburg effect), impaired angiogenesis, phenotypic transition, and chronic inflammation [3,4,5,6,7,8,9,10,11,12,13,14]. Currently, no cure exists for PAH and most therapies targeting vasoconstriction, while offering symptomatic improvement and delaying clinical worsening, do not effectively reverse this devastating disease [2,15]. Indeed despite recent improvements in therapies, the estimated survival rate of patients affected by PAH is 50%–70% at 3 years [16]. Therefore, a better understanding of PAH pathogenesis is mandatory to identify new therapeutic targets capable of interrupting the disease process.

Despite a poor knowledge of the events occurring in early stages of PAH, mounting evidence indicates that oxidative stress and inflammation significantly contribute to vascular remodeling by promoting exaggerated contractility and proliferation of vascular cells [17,18]. These factors are also known to favor DNA damages. Indeed, the DNA sequence can be altered by error-prone DNA polymerases during replication or by environmental factors such as mutagenic chemicals, oxidative stress, radiations, and chronic inflammation. If these damages are not correctly repaired, cells accumulate mutations in their genome, which can lead to death by apoptosis or in some cases to an altered phenotype as observed in cancer [19]. Increased environmental factors and/or dysfunctional DNA-damage response mechanisms may therefore promote the emergence of an apoptosis-resistant and hyper-proliferative phenotype implicated in vascular remodeling [20]. The present review provides an overview of recent insights showing that DNA damage contributes to PAH pathogenesis.

2. DNA Damage and Repair

DNA is chemically unstable in physiological conditions, like all biological macromolecules, and is vulnerable to hydrolysis, oxidation, and non-enzymatic methylation [21]. In addition to its intrinsic tendency to decompose, DNA lesions arise from endogenous and exogenous genotoxic agents. Endogenous genotoxic substances are produced by cellular metabolism, which is a source of reactive nitrogen and oxygen species (RNS and ROS), estrogen metabolites, and endogenous reactive chemicals such as aldehydes produced by lipid peroxidation [22] or alkylating molecules like S-adenosylmethionines involved in gene expression regulation through physiological DNA methylation [23,24]. Exogenous genotoxic agents refer to environmental events such as exposure to mutagenic chemicals or physical agents like UV or ionizing radiation (e.g., X-rays) [25,26]. Resulting DNA damages can be single-strand (SSBs) or double strand breaks (DSBs), abasic site (also known as AP site (apurinic/apyrimidinic site)), modified bases, bulky adducts, interstrand/intrastrand crosslinks or insertion of intercalating agents [19,26,27,28,29,30,31,32,33].

DNA integrity is constantly threatened. SSBs, which are the most common type of DNA damage, occur more than 104 times per cell per day, only from endogenous DNA insults and spontaneous DNA decay [30,34]. Taken together, the estimated rate of spontaneous DNA lesions is around 105 per cell per day [25]. The fate of cells against constant DNA damage lies on efficient repair mechanisms called DNA-damage response (DDR). DDR involves multiple pathways for rapid detection, signaling and repair of DNA lesions [35,36,37].

2.1. Single-Strand Damage

SSBs are the most common DNA lesions. In this type of lesion only one of the two DNA strands has a defect with a missing or damaged nucleotide and altered 5′ and/or 3′ ends at the lesion site [30]. SSBs may results from attack of DNA bases and deoxyribose by ROS or other electrophilic molecules [38]. Three excision repair pathways exist to repair this type of alteration in DNA integrity, which are base excision repair (BER), nucleotide excision repair (NER) and mismatch repair (MMR).

BER is a pathway involved in resolving non-bulky DNA lesions by excising and replacing abnormal or damaged DNA bases (methylated, oxidized or reduced bases). During BER, the incorrect or damaged base is excised by DNA glycosylases then replaced by DNA polymerases and ligases [39,40,41,42,43]. Poly(ADP-ribose) polymerase 1 (PARP1) can accelerate BER. PARP can bind on AP sites obtained following DNA glycosylases excision [30,44,45]. When fixed, PARP1 synthesizes branched chains of poly(ADP)ribose (pADPr) polymers. pADPr allows the recruitment of X-ray repair cross-complementing protein 1 (XRCC1) scaffolding protein in complex with polynucleotide kinase (PNK), DNA polymerase β and DNA ligase III [46,47,48,49]. pADPr polymers can give hundreds of ADPr monomers, which negatively charge the SSB site. Accumulation of negative charges opens the DNA strands, stabilizes them, and therefore facilitates BER repair. It also releases PARP1 from the AP site, which is then restored by Poly(ADP-ribose) glycohydrolase [30,50,51,52].

Pathways involved in DNA lesions detection for the NER mechanism are mainly important for DNA damage induced by UV. They rely on damage sensor Xeroderma pigmentosum complementation group C and other proteins recruited at the lesion site, such as Cockayne syndrome protein [53,54,55]. Mutations in these NER proteins lead to severe diseases like xeroderma pigmentosum, Cockayne syndrome or trichothiodystrophy [56].

The MMR pathway recognizes base-base mismatches and insertion/deletion loops due to partnerless nucleotides that appear during DNA replication [54,57,58,59,60,61,62]. Mutations on genes that code for proteins involved in MMR is linked to hereditary nonpolyposis colorectal cancer hereditary cancers [59,63,64].

2.2. Double-Strand Breaks

DSBs leave no complementary strand that can be used as template during repair. They represent a more serious threat for DNA integrity as they can lead to chromosome breaks and translocation. Three major pathways are implicated in DSB repair: non-homologous end joining (NHEJ), homologous recombination (HR), and to a lesser extent microhomology-mediated end joining (MMEJ).

In the classical NHEJ pathway, Ku70/86 heterodimer binds to the broken DNA strands and forms a complex with DNA-dependent protein kinase. After recruiting other proteins to the damaged site, a DNA ligase IV will seal both ends of DNA strands [65,66,67,68,69,70]. An alternative NHEJ pathway also occurs in cells with deficient classical NHEJ. The alternative NHEJ may also implicate PARP1, which is implicated in SSB repair as described above. PARP1 binds at the DSBs site and may recruit the Mre11-Rad50-Nbs1 complex and scaffolding protein XRCC1/DNA ligase III complex to ligate DNA ends. Nevertheless, the alternative NHEJ pathway leads to large deletion of DNA sequences, rearrangements, and chromosomal translocation as well as being involved in cancer cell pro-survival phenotype [66,67,68,71,72,73,74,75,76,77,78,79].

HR is involved in DSBs and interstrand crosslinks repair. It occurs between late S phase and G2 phase of the cell cycle and is a less error-prone repair pathway than NHEJ. The HR begins with a resection step to produce a 3′ single-stranded DNA end. The protein Rad51 interacts with Rad52, BRCA1, and BRCA2 (breast cancer 1 and 2) to create nucleoprotein filaments that drive strand invasion to the homologous one from the partner chromatid in a displacement loop structure. The lesion site is then repaired using the homologous DNA template [68,80,81,82,83,84,85,86,87,88,89]. The choice between NHEJ and HR depends on the cell cycle phase as well as regulatory factors such as p53-binding protein 1 (53BP1) or BRCA1. Thereby it appears that 53BP1 will favor NHEJ whereas BRCA1 will promote HR [88,90,91,92]. Nevertheless, their implication is not well understood as BRCA1 may also play an accessory role in NHEJ [93]. Both 53BP1 and BRCA1 deficiencies have been linked to cancer development suggesting that both HR and NHEJ are required for genome stability [87,94,95,96].

MMEJ relies on microhomologies of 2–20 bp in both DNA strands. This mechanism is still unclear but among others, PARP1 may also play a role in this type of repair [77,97,98,99]. It appears that DNA polymerase θ also promotes MMEJ and inhibits homologous recombination [77,100]. MMEJ is an error-prone DNA repair pathway that favors oncogenic translocations and cancer development [77,98], and overexpression of DNA polymerase θ gene POLQ is associated with poor survival [101,102].

3. DNA Damage in Pulmonary Arterial Hypertension

3.1. Evidences DNA Damage in PAH

First evidences of somatic genetic mutations involved in PAH pathogenesis were reported in 1998 as a monoclonal origin of PAECs found in plexiform lesions in idiopathic and appetite suppressant-associated PAH [103,104]. Moreover, microsatellite instabilities were observed in growth and death regulation genes in PAECs from plexiform lesions [105]. Somatic mutations in PAECs are not specific to plexiform lesions as severe genetic abnormalities were also observed in more than half of PAH patients’ PAECs and in explanted tissues [106]. Federici and colleagues [107] observed chromosomal abnormalities in 30.2% of PAH-PAECs versus 5.3% in control PAECs. Interestingly, DNA damage was not specific to the lung vasculature as it was also increased in lymphoblastoid cell lines and peripheral blood cells from PAH patients when compared to control subjects. Increased mutagen sensitivity to etoposide and bleomycin was also observed in peripheral blood mononuclear cells from PAH patients and non PAH relatives compared to controls [107]. These observations support the hypothesis of a predisposed sensitivity to DNA damage induced by the PAH environment that may act as a trigger of the pathogenesis.

3.2. Inflammation

Inflammation is one of PAH hallmarks and is strongly associated with its pathogenesis. PAH can occur as a complication of various systemic inflammatory conditions such as lupus erythematosus, scleroderma, mixed connective tissue disease, Hashimoto thyroiditis, Castleman disease, POEMS syndrome, human immunodeficiency virus (HIV) infection, and autoimmunity [108]. In some cases, the use of anti-inflammatory therapies can improve patients’ conditions [109,110,111,112].

Regardless of the associated diseases, inflammation is present around remodeled vessels in PAH patients’ lungs. Indeed, there is accumulation of perivascular inflammatory cells such as B and T lymphocytes, mast and dendritic cells, and lymphoid follicles [6,113,114,115,116,117,118,119]. Inflammation in PAH is also associated with increased levels of pro-inflammatory cytokines, such as IL1-β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, and tumor necrosis factor α (TNF-α) [120,121,122]. Some cytokines seem to be good indicators of PAH progression like the monocyte chemoattractant protein-1 (MCP-1), which is upregulated in early stage of PAH [123] or like IL-6, IL-8, IL-10, and IL-12 that increase with PAH severity and appear to be markers of poor survival rate [121].

Preclinical data also demonstrate that inflammation is strongly implicated in the development of pulmonary vascular remodeling. Indeed, IL-6 administration or overexpression in rodent is sufficient to induce pulmonary vascular remodeling and to exacerbate chronic hypoxia-induced PH [124,125,126]. Conversely, IL-6 knockout mice are less susceptible to develop PH under hypoxia [127]. Inflammation favors pro-proliferation and pro-survival phenotypes but also DNA damage through increased ROS/RNS levels produced by vascular cells under inflammatory condition or massively released by neutrophils and macrophages recruited at inflammation sites. ROS/RNS damage DNA through DNA base oxidation and deamination, or through lipid peroxidation and base alkylation [128]. Among PAH-associated cytokines, TNF-α is linked to increased oxidative DNA damage in hepatocytes and myocytes, and inflammation-associated cancers via activation of the transcription factor NF-κB (nuclear factor-κB), which promotes cell survival [129,130,131,132]. ROS/RNS and DNA damage also promote directly or indirectly DDR, which induces inflammation in a vicious cycle that is known to promote aging and carcinogenesis [24,128,133,134,135,136,137]. For example, DNA damage induces IL-6 production which promotes survival and proliferation though activation of the JAK1-STAT3 signaling pathway in tumor cells [138,139,140].

Inflammation in PAH may also be modulated by alterations in the bone morphogenetic protein receptor type II (BMPR2) signaling pathway. BMPR2 loss-of-function mutations increase susceptibility to PAH [141], and BMPR2 pathway alterations are key features observed in PAH, contributing to aberrant inflammatory response through altered cytokines feedback regulation like the one described in vivo and in vitro for IL-6 in PASMCs [142,143]. For instances, reduced BMPR2 gene dosage (BMPR2+/−) in mice elicits a stronger inflammatory response after LPS (Lypopolysaccharide) exposure [144]. Similar results were observed in PAH-PASMCs harboring a BMPR2 mutation. The LPS inflammatory response in PASMCs isolated from BMPR2+/− mice and from PAH patients carrying BMPR2 mutations was associated with a reduced expression of extracellular superoxide dismutase 3 and increased activation of STAT3 [144]. Superoxide dismutase 3 is an antioxidant that prevents oxidative damage and STAT3 was found to be a major signaling component downstream of diffusible factors dysregulated in PAH (like TNF, IL-6 and PDGF-β) and enhancing proliferation and resistance to apoptosis [144,145,146]. In this study, chronic exposure to LPS leads to PH development in of BMPR2+/− mice but not in controls, whereas PH and increased inflammation were prevented by tempol treatment, a superoxide dismutase mimetic, confirming the vicious cycle of chronic inflammation and oxidative stress in this PH model [144].

3.3. Oxidative Stress

Oxidative stress is characterized by an increased production of oxidants species and/or decreased production of antioxidants. It is associated with increased ROS and RNS as well as decreased nitric oxide (NO) bioavaibility. Oxidative stress seems to play a crucial role in PH [147,148,149,150] as it can favor vessel thickening by increasing transforming growth factor-β1 (TGF-β1), vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2) [151], and platelet-derived growth factor (PDGF) production [152], as well as by mediating endothelin-1-induced PASMCs proliferation [153]. ROS also upregulate hypoxia-inducible transcription factors HIF-1α and HIF-2α expression [154,155] also implicated in PAH development [156,157]. In addition, oxidative stress can also promote vasoconstriction via increased production of endothelin-1 [158] and thromboxane A2 [159], decreased production of prostacyclin [160,161], and increased hypoxic cytosolic Ca2+ concentration in PASMCs [162,163]. In agreement with the crucial role of oxidative stress in the pathogenesis of PAH [164,165,166,167,168], antioxidant therapy was reported to have beneficial effects in animal models of the disease [169,170,171,172].

The oxidative stress observed in PH is produced by both inflammatory and vascular cells. Indeed, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, which are important sources of ROS, are found in macrophages and polymorphonuclear as well as in PAECs, PASMCs and fibroblasts [147,173,174,175]. In the lung vasculature, NADPH oxidases 1–5 play a crucial role in increasing ROS generation and promoting vascular dysfunction in PH models. Under hypoxia, NADPH oxidases 2 has been linked to EC dysfunction and vascular ROS production [176] and its upregulation and activation have been linked to neointima formation in animal models [177]. NADPH oxidases 4 upregulation in PAH and under hypoxia has been associated to adventitial fibroblasts resistance to apoptosis and adventitial fibroblasts and PASMC proliferation [173,178]. Interestingly, increased level of TGF-β1, as observed in PAH serum, leads to NADPH oxidases 4 upregulation in PASMCs [179,180]. Vascular ROS can also be produced in ECs by endothelial nitric oxide synthase under L-arginine or cofactor (BH4) depletion condition. In these cases, “uncoupled” endothelial nitric oxide produces ROS rather than NO [181]. l-Arginine deficiency can be the result of decreased l-arginine production, increased production/activity of arginase or increased analog competition with asymmetric dimethyl-l-arginine (ADMA). Elevated plasma arginase activity was reported in sickle cell disease-associated PH [182] and increased level of ADMA associated to reduced ADMA catabolism by dimethylarginine dimethylaminohydrolase 2 was linked to PH [183,184,185]. Finally, ROS accumulation can be the result of impaired ROS scavenging system. Indeed, one of the major antioxidants implicated, the superoxide dismutase 2, was found down-expressed in plexiform lesions and within the media and adventitia of remodeled small arteries from PAH patients [186]. Moreover, as described above, BMPR2 deficiency has also been associated with reduced expression of antioxidant superoxide dismutase 3 in BMPR2+/− mice exposed to LPS [144].

Increased oxidative stress leads to inflammation and cell injuries due to oxidation of proteins, lipids and DNA, which is observed in PAH patients [148,187,188,189,190,191]. The major oxidative DNA lesion is produced by oxidation of guanine into 8-hydroxydeoxy guanosine, which can produce mutations after DNA repair by G:C to T:A transversions [192,193,194]. It was recently published that DNA damages observed in PAH-PAECs and PAH-lymphoblastoid cell lines were associated with increased levels of ROS [107].

3.4. Anorexigen Drugs and Selective Serotonin Reuptake Inhibitors

The prescription of Aminorex, fenfluramines derivatives and Benfluorex used as appetite suppressants was followed by PAH epidemics [195,196,197]. All these molecules share structural and pharmaceutical similarities with amphetamine derivatives which are also considered to be risk factors for PAH [108,198,199,200,201]. Fenfluramines, amphetamines and derivatives had been reported to induce systemic DNA damages through oxidative stress [202,203,204,205,206,207,208,209,210,211]. Fenfluramine derivatives are also substrates for the serotonin transporter and potent serotonin uptake inhibitors [201,212]. More recently, the use of selective serotonin-reuptake inhibitors (SSRIs) in late pregnancy was associated with an increase in the prevalence of persistent pulmonary hypertension of the newborn [213,214] as well as clinical worsening and increased mortality in PAH patients [215]. Dhalla and colleagues [216] reported a positive association between SSRIs use and PAH. The serotonin and serotonin transporter (5-HTT) are implicated in PAH pathogenesis by promoting PASMC proliferation and vasoconstriction. 5-HTT expression and activity are found increased in platelets and PH lungs. The use of 5-HTT inhibitor reduces the proliferation of PASMCs induced by serum and serotonin [217] and its knock out in 5-HTT−/− mice was reported to attenuate hypoxic PH [218]. Thus, it has been speculated that SSRIs might increase extracellular serotonin levels that affect PASMCs [212]. Indeed PAH patients are more susceptible to serotonin-induced PASMCs proliferation as 5-HTT expression and activity are found increased in platelets and PAH lungs. This predisposition can be explained by long allelic variants of the 5-HTT gene promoter that lead to increased 5-HTT expression in PASMCs. A study from Eddahibi and colleague [217] reported that 65% of PAH patients presented homozygous long allelic variants compared to 27% of controls. Interestingly, SSRIs are also known to have genotoxic effects in patients and animal models [219,220,221,222,223,224]. Although dysregulation of serotonin synthesis in PAH development is well established, SSRIs implication in early PAH pathogenesis is still debated. In a recent study, Fox et al. reported that both SSRIs and non-SSRIs antidepressant treatments are associated with the same increased risk of PAH [225]. Moreover the absence of correlations between the potency of 5-HTT inhibition or the duration of treatment and the risk of PAH development suggest a non-causal association. Thus the authors suggested that depressive symptoms may be a risk factor of PAH as altered serotonin signaling predisposes to both conditions [225]. Interestingly, in addition to deleterious effects of dysregulated serotonin signaling on lung vasculature, it appears that depressive disorder also leads to increased DNA damage and DDR deficiency [226,227].

3.5. Alkylating Chemotherapies

Alkylating agents are antineoplastic molecules used to treat several cancers. They react with guanine base of DNA to create covalent bonds [228]. Depending on their structure, these agents can modify one nucleotide (monofunctional alkylating agent) or two nucleotides (bifunctional alkylating agents) which, in this case, can create interstrand DNA crosslinks [229,230]. If not repaired, these DNA alterations lead to cell death. In healthy cells, BER, NER, and MMR pathways can efficiently remove these alterations. However, cancer cells will be heavily damaged because of their high proliferative phenotype and DDR deficiency (less error-correcting capacity). Nevertheless, the nonspecific action of alkylating agents can also induce mutations in healthy cells with rapid division. Alkylating agents are also known to cause severe injuries to hepatic and pulmonary ECs [231,232]. It was recently published that the use of bifunctional alkylating agents used in chemotherapies were associated with the development of pulmonary veno-occlusive disease (PVOD), an uncommon form of PAH both in human and animals [233,234,235]. The use of mitomycin C, was associated with high risk of anal cancer-associated PVOD (3.9/1000 per year) in comparison with the rare incidence of PVOD in the general population (<1/million per year) [234]. This side effect could be explained by selective toxicity of mitomycin C towards cells expressing high level of the mitomycin C-activating enzyme, NAD(P)H:quinone oxidoreductase. Indeed, NAD(P)H:quinone oxidoreductase is overexpressed in various cancers, but also highly expressed in normal pulmonary vascular endothelium [236]. The pulmonary vascular toxicity of cyclophosphamide could be explained by the lack of detoxifying enzymes, such as aldehyde oxidase and aldehyde dehydrogenase [237] and by endothelial sensitivity to cyclophosphamide-induced damage [238,239]. In addition to DNA alterations, it was noted that in vitro cyclophosphamide treatment depleted glutathione in hepatic sinusoidal endothelial cells favoring oxidative stress [240,241,242]. PVOD is also linked to occupational exposures to organic solvents such as trichloroethylene also know to induce DNA damages [243,244]. Interestingly, monocrotaline, a plant toxin used to induce PH in rats, becomes active after it is metabolized in dehydromonocrotaline, a bifunctional alkylating agent, that induces vascular damage [245,246,247]. Alkylating agents may therefore damage the vascular endothelium and limit its repair capacity by inhibiting the proliferation of remaining PAECs. This may lead to a delayed pulmonary vascular injury, progressive remodeling, and PAH.

4. DNA Repair Mechanisms in PAH Pathogenesis

DDR dysregulation has also been recently identified as a trigger involved in PAH pathogenesis. Meloche et al. [248] reported that DNA damage in PAH was associated with PARP1 overexpression in PASMCs due to a decrease in miR-223 expression [249]. PARP1 maintains cell survival in a context of DNA damage but can also lead to increased levels of IL-6, inflammation and apoptosis resistance via miR-204/STAT3 mediated activation of bromodomain-containing protein 4 (BRD4), nuclear factor of activated T-cells (NFAT), and HIF-1α [248,250,251]. PARP1 inhibition by ABT-888 has been shown to reverse PH in two animal models of the disease (monocrotaline- and Sugen/hypoxia-induced PH) [248]. Moreover, as previously described, PARP1 is implicated in MMEJ and alternative NHEJ, which are known to induce errors, DNA sequences deletions, rearrangements, and chromosomal translocation [98,99,252,253,254,255]. Similar observations were made with Pim1 and Survivin, two onco-proteins overexpressed during DDR activation, associated to increased DNA repair [256,257]. Their overexpression in PAH PASMC and monocrotaline rat remodeled arteries was linked to increased apoptosis resistance, proliferation, and inflammation which were attenuated by their inhibition [258,259].

It has also been described that loss of BMPR2, can lead to impaired DNA damage repair [260]. In this article, Li and colleagues [260] reported how downregulation of BMPR2 in PAH PAECs decreased BRCA1 expression and increased susceptibility to DNA damages. BRCA1 expression was found decreased in endothelium from PAH remodeled vessels compared to control ones [260]. As previously described, BRCA1 is implicated in HR and NHEJ, but its role remains unclear. Whole-exome sequencing has recently led to the discovery of mutations in another gene, topoisomerase DNA II binding protein 1 (TopBP1), also involved in PAH susceptibility [261]. Alteration of TopBP1 expression was found in situ in PAECs from idiopathic PAH patients’ lungs. TopBP1 is important in maintaining genome integrity by preventing DNA damage during replication [262,263,264]. In this article [261], siRNA knockdown of TopBP1 resulted in increased DNA damage sensitivity and apoptosis in healthy pulmonary microvascular ECs, whereas its restoration using plasmids in idiopathic PAH microvascular ECs decreased hydroxyurea-induced DNA damage and improved cell survival. The link between newly discovered PAH susceptibility genes and DDR strengthens the fact that impaired DNA repair is involved in PAH susceptibility. Interestingly, PH can spontaneously occur in animal models of impaired DDR. It has been reported that Ku70−/− mice, that display impaired NHEJ and genome instability, spontaneously develop severe pulmonary vessels remodeling and PAH [265]. Chronic inhibition of p53, also involved in NHEJ, with pifithrin-α was sufficient to induced PH in rats [266]. p53 knockout also increases hypoxia-induced PH in mice [267]. Lastly, activation of p53 pathway by Nutlin-3a treatment was reported to reduce PH in an animal model [268].

Finally, as summarized in a review by Potus et al. [269], DDR is complex and its activation can modify micro-RNA pathways that are impaired in PAH [270]. Moreover nuclear DDR also affects, via the nucleus to mitochondria signaling, the mitochondrial function and mitophagy [271].

5. DNA Damage: Beyond the Nucleus

Mitochondrial dysfunction has been linked to cancer [272,273] as well as vascular and lung diseases including PAH [274,275,276,277,278]. ECs mainly use glycolysis and do not rely on mitochondrial metabolism. It has been suggested that endothelial mitochondria mainly serve as signaling organelles for hypoxic response, inflammation, apoptosis, and vasoconstriction [275,277,279,280,281]. PAH patients display dysmorphic, hyperpolarized mitochondria, mitochondrial fission, mitochondria–Endoplasmic Reticulum Unit disruption, and metabolic switch from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis (Warburg effect) [277,282,283,284,285,286]. Similar observations of abnormal mitochondria were made in Fawn-Hooded rats, a rat strain with disrupted mitochondria-ROS-HIF-Kv pathway that spontaneously develops PAH [282,287,288]. The use of dichloroacetate, a mitochondrial pyruvate dehydrogenase kinase inhibitor, improves Fawn-Hooded rats-PAH as well as PH induced by chronic hypoxia or monocrotaline [282,289,290] confirming the role of mitochondria dysfunction in PH development. Interestingly, it has been reported that altered BMPR2 expression was also linked to PAECs mitochondrial dysfunction [291,292]. Altered mitochondria is also implicated in PASMCs apoptosis resistance [284,285] and in right ventricle dysfunction that occurs in PAH and monocrotaline-induced PH [293,294,295].

Interestingly, mitochondria are more sensitive to DNA damage, compared to nuclear DNA since they lack protective histones and their DDR mechanisms only rely on BER and MMEJ [296,297,298,299]. Moreover, it has been reported that mitochondrial DNA (mtDNA) damage repair in PAECs was somewhat slower compared to pulmonary venous ECs and microvascular ECs [300] suggesting that mtDNA damage might be implicated in PAH. Furthermore, mtDNA damage has a potential role in diseases associated with increased risk for PAH such as systemic lupus erythematosus [301,302,303,304]. In a recent study, Fetterma and colleagues [304] found that increased mtDNA damage in atherosclerosis and diabetes mellitus was associated with increased arterial baseline pulse amplitude suggesting a link between mtDNA damage and excessive microvascular pulsatility. Sirtuin 3, a mitochondrial protein among others involved in mtDNA repair via 8-Oxoguanine glycosylase 1 [305] is downregulated in PAH patients and monocrotaline-induced PH rat whereas Sirtuin 3 knockout mice spontaneously develop PAH [306]. In human glioblastoma cell lines, Sirtuin 3 depletion increased irradiation-induced oxidative damage to mtDNA [305]. DDR in mitochondria is less understood and differs from nuclear DDR since similar proteins may have opposite effects on DNA integrity as observed with PARP1 [307,308]. While a role of mtDNA damage in the development and progression of PAH is speculated, further investigations aiming to demonstrate the presence and effects of mtDNA damage in PAH cells remain to be performed.

6. Conclusions

DNA damage is increased in human PAH lungs, remodeled arteries, PASMCs as well as PAECs. PBMCs also exhibit increased DNA damage, suggesting that this phenomenon is not restricted to the pulmonary vasculature and that intrinsic mutagen sensitivity is present in these patients. Recent studies have found that PAH patients display impaired DNA damage repair associated with TopBP1 and BMPR2-mediated BRCA1 down-expressions. Mutations in TopBP1 and BMPR2 genes are associated to PAH predisposition. These DDR alterations lead to genome instability in the PAH environment that favors DNA damage. Indeed the pathogenesis involves chronic inflammation and oxidative stress that are strongly associated with increased DNA damage. In addition, PAH has been linked to drugs such as anorexigen and SSRIs that have genotoxic side effects. Moreover, endothelial DNA damage due to exposure of alkylating agents such as cyclophosphamide or mytomycin C also favors PAH. As in cancer, increased DNA damage and/or impaired DNA repair may promote the proliferative and apoptosis-resistant phenotype that characterizes PAH vascular cells. The implication of DNA damage was also reported in PH animal models reinforcing the observations made in human PAH. DDR mechanisms are complex and interact with cellular pathways that promote directly or indirectly proliferation and apoptosis resistance implicated in PAH development. As described previously for PARP1, DDR also promotes inflammation and therefore DNA damage in a vicious circle. All these evidences summarized in the present review (Figure 1) support the hypothesis that DNA damage sensitivity may act as an early trigger of PAH. Both nuclear and mitochondrial DDR are still not well characterized and crosstalk between them or with other pathological pathways may also be involved in the pathogenesis. Further studies are then required to fully explain how DNA damage and DDR contribute to PAH pathogenesis in order to identify new therapeutic targets.

Figure 1
DNA damage and DNA-damage response mechanisms directly or indirectly involved in PAH pathogenesis via PAEC dysfunction and PASMC proliferation and apoptosis resistance (red). PAEC: pulmonary artery endothelial cell; PASMC: pulmonary artery smooth muscle ...

Acknowledgments

Jolyane Meloche was awarded a Fonds de recherche du Québec—Santé (FRQS) PhD scholarship. Steeve Provencher is a FRQS clinical scientist. Sébastien Bonnet holds a Canadian research chair. Canadian Institutes of Health Research grants and Heart and Stroke Foundation of Canada to Steeve Provencher and Sébastien Bonnet supported this work.

Abbreviations

ADMAasymmetric dimethyl-l-arginine
AP siteapurinic/apyrimidinic site; abasic site
BERbase excision repair
BRCA1breast cancer 1
DDRDNA-damage response
DSBDNA double strand breaks
ECendothelial cell
HRhomologous recombination
MMEJmicrohomology-mediated end joining
MMRmismatch repair
NERnucleotide excision repair
NHEJnon-homologous end joining
PAECpulmonary artery endothelial cell
PAHpulmonary arterial hypertension
PARP1poly(ADP-ribose) polymerase 1
PASMCpulmonary artery smooth muscle cell
PHpulmonary hypertension
RNSreactive nitrogen species
ROSreactive oxygen species
SSBDNA single-strand break

Author Contributions

Author Contributions

Benoît Ranchoux, Jolyane Meloche, Roxane Paulin, Olivier Boucherat, Steeve Provencher and Sébastien Bonnet wrote the paper

Conflicts of Interest

Conflicts of Interest

The authors declare no conflict of interest.

References

1. Hoeper M.M., Humbert M., Souza R., Idrees M., Kawut S.M., Sliwa-Hahnle K., Jing Z.-C., Gibbs J.S.R. A global view of pulmonary hypertension. Lancet Respir. Med. 2016 doi: 10.1016/S2213-2600(15)00543-3. [PubMed] [Cross Ref]
2. Hoeper M.M., McLaughlin V.V., Dalaan A.M.A., Satoh T., Galiè N. Treatment of pulmonary hypertension. Lancet Respir. Med. 2016 doi: 10.1016/S2213-2600(15)00542-1. [PubMed] [Cross Ref]
3. Tuder R.M., Archer S.L., Dorfmüller P., Erzurum S.C., Guignabert C., Michelakis E., Rabinovitch M., Schermuly R., Stenmark K.R., Morrell N.W. Relevant issues in the pathology and pathobiology of pulmonary hypertension. J. Am. Coll. Cardiol. 2013;62:D4–D12. doi: 10.1016/j.jacc.2013.10.025. [PMC free article] [PubMed] [Cross Ref]
4. Humbert M., Montani D., Perros F., Dorfmüller P., Adnot S., Eddahibi S. Endothelial cell dysfunction and cross talk between endothelium and smooth muscle cells in pulmonary arterial hypertension. Vascul. Pharmacol. 2008;49:113–118. doi: 10.1016/j.vph.2008.06.003. [PubMed] [Cross Ref]
5. Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J. Clin. Investig. 2012;122:4306–4313. doi: 10.1172/JCI60658. [PMC free article] [PubMed] [Cross Ref]
6. Cohen-Kaminsky S., Hautefort A., Price L., Humbert M., Perros F. Inflammation in pulmonary hypertension: What we know and what we could logically and safely target first. Drug Discov. Today. 2014;19:1251–1256. doi: 10.1016/j.drudis.2014.04.007. [PubMed] [Cross Ref]
7. Ryan J., Dasgupta A., Huston J., Chen K.-H., Archer S.L. Mitochondrial dynamics in pulmonary arterial hypertension. J. Mol. Med. 2015;93:229–242. doi: 10.1007/s00109-015-1263-5. [PMC free article] [PubMed] [Cross Ref]
8. Potus F., Ruffenach G., Dahou A., Thebault C., Breuils-Bonnet S., Tremblay È., Nadeau V., Paradis R., Graydon C., Wong R., et al. Downregulation of MicroRNA-126 Contributes to the Failing Right Ventricle in Pulmonary Arterial Hypertension. Circulation. 2015;132:932–943. doi: 10.1161/CIRCULATIONAHA.115.016382. [PubMed] [Cross Ref]
9. Potus F., Malenfant S., Graydon C., Mainguy V., Tremblay È., Breuils-Bonnet S., Ribeiro F., Porlier A., Maltais F., Bonnet S., et al. Impaired angiogenesis and peripheral muscle microcirculation loss contribute to exercise intolerance in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 2014;190:318–328. doi: 10.1164/rccm.201402-0383OC. [PubMed] [Cross Ref]
10. Ranchoux B., Antigny F., Rucker-Martin C., Hautefort A., Péchoux C., Bogaard H.J., Dorfmüller P., Remy S., Lecerf F., Planté S., et al. Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation. 2015;131:1006–1018. doi: 10.1161/CIRCULATIONAHA.114.008750. [PubMed] [Cross Ref]
11. Kherbeck N., Tamby M.C., Bussone G., Dib H., Perros F., Humbert M., Mouthon L. The role of inflammation and autoimmunity in the pathophysiology of pulmonary arterial hypertension. Clin. Rev. Allergy Immunol. 2013;44:31–38. doi: 10.1007/s12016-011-8265-z. [PubMed] [Cross Ref]
12. Malenfant S., Neyron A.-S., Paulin R., Potus F., Meloche J., Provencher S., Bonnet S. Signal transduction in the development of pulmonary arterial hypertension. Pulm. Circ. 2013;3:278–293. doi: 10.4103/2045-8932.114752. [PMC free article] [PubMed] [Cross Ref]
13. Perros F., Humbert M., Cohen-Kaminsky S. Pulmonary arterial hypertension: A flavor of autoimmunity. Méd. Sci. 2013;29:607–616. [PubMed]
14. Montani D., Günther S., Dorfmüller P., Perros F., Girerd B., Garcia G., Jaïs X., Savale L., Artaud-Macari E., Price L.C., et al. Pulmonary arterial hypertension. Orphanet J. Rare Dis. 2013;8:97. doi: 10.1186/1750-1172-8-97. [PMC free article] [PubMed] [Cross Ref]
15. Montani D., Chaumais M.-C., Guignabert C., Günther S., Girerd B., Jaïs X., Algalarrondo V., Price L.C., Savale L., Sitbon O., et al. Targeted therapies in pulmonary arterial hypertension. Pharmacol. Ther. 2014;141:172–191. doi: 10.1016/j.pharmthera.2013.10.002. [PubMed] [Cross Ref]
16. Humbert M., Sitbon O., Chaouat A., Bertocchi M., Habib G., Gressin V., Yaïci A., Weitzenblum E., Cordier J.-F., Chabot F., et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010;122:156–163. doi: 10.1161/CIRCULATIONAHA.109.911818. [PubMed] [Cross Ref]
17. Rabinovitch M., Guignabert C., Humbert M., Nicolls M.R. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ. Res. 2014;115:165–175. doi: 10.1161/CIRCRESAHA.113.301141. [PMC free article] [PubMed] [Cross Ref]
18. Intengan H.D., Schiffrin E.L. Vascular remodeling in hypertension: Roles of apoptosis, inflammation, and fibrosis. Hypertension. 2001;38:581–587. doi: 10.1161/hy09t1.096249. [PubMed] [Cross Ref]
19. Lodish H., Berk A., Zipursky S.L., Matsudaira P., Baltimore D., Darnell J. Molecular Cell Biology. W.H. Freeman; New York, NY, USA: 2000. DNA Damage and Repair and Their Role in Carcinogenesis.
20. Vaillancourt M., Ruffenach G., Meloche J., Bonnet S. Adaptation and remodelling of the pulmonary circulation in pulmonary hypertension. Can. J. Cardiol. 2015;31:407–415. doi: 10.1016/j.cjca.2014.10.023. [PubMed] [Cross Ref]
21. Lindahl T. Instability and decay of the primary structure of DNA. Nature. 1993;362:709–715. doi: 10.1038/362709a0. [PubMed] [Cross Ref]
22. Esterbauer H., Eckl P., Ortner A. Possible mutagens derived from lipids and lipid precursors. Mutat. Res. 1990;238:223–233. doi: 10.1016/0165-1110(90)90014-3. [PubMed] [Cross Ref]
23. Holliday R., Ho T. Gene silencing and endogenous DNA methylation in mammalian cells. Mutat. Res. 1998;400:361–368. doi: 10.1016/S0027-5107(98)00034-7. [PubMed] [Cross Ref]
24. De Bont R., van Larebeke N. Endogenous DNA damage in humans: A review of quantitative data. Mutagenesis. 2004;19:169–185. doi: 10.1093/mutage/geh025. [PubMed] [Cross Ref]
25. Hoeijmakers J.H.J. DNA damage, aging, and cancer. N. Engl. J. Med. 2009;361:1475–1485. doi: 10.1056/NEJMra0804615. [PubMed] [Cross Ref]
26. Ribezzo F., Shiloh Y., Schumacher B. Systemic DNA damage responses in aging and diseases. Semin. Cancer Biol. 2016 doi: 10.1016/j.semcancer.2015.12.005. [PMC free article] [PubMed] [Cross Ref]
27. Helleday T., Eshtad S., Nik-Zainal S. Mechanisms underlying mutational signatures in human cancers. Nat. Rev. Genet. 2014;15:585–598. doi: 10.1038/nrg3729. [PubMed] [Cross Ref]
28. Lindahl T., Nyberg B. Rate of depurination of native deoxyribonucleic acid. Biochemistry. 1972;11:3610–3618. doi: 10.1021/bi00769a018. [PubMed] [Cross Ref]
29. Boiteux S., Guillet M. Abasic sites in DNA: Repair and biological consequences in Saccharomyces cerevisiae. DNA Repair. 2004;3:1–12. doi: 10.1016/j.dnarep.2003.10.002. [PubMed] [Cross Ref]
30. Caldecott K.W. Single-strand break repair and genetic disease. Nat. Rev. Genet. 2008;9:619–631. [PubMed]
31. Negritto C. Double-Strand Breaks in DNA Can Be Lethal to a Cell. How Do Cells Fix Them? [(accessed on 23 March 2016)]. Available online: http://www.nature.com/scitable/topicpage/repairing-double-strand-dna-breaks-14432332.
32. Stingele J., Jentsch S. DNA-protein crosslink repair. Nat. Rev. Mol. Cell Biol. 2015;16:455–460. doi: 10.1038/nrm4015. [PubMed] [Cross Ref]
33. Noll D.M., Mason T.M., Miller P.S. Formation and repair of interstrand cross-links in DNA. Chem. Rev. 2006;106:277–301. doi: 10.1021/cr040478b. [PMC free article] [PubMed] [Cross Ref]
34. Lenart P., Krejci L. DNA, the central molecule of aging. Mutat. Res. 2016;786:1–7. doi: 10.1016/j.mrfmmm.2016.01.007. [PubMed] [Cross Ref]
35. Rouse J., Jackson S.P. Interfaces between the detection, signaling, and repair of DNA damage. Science. 2002;297:547–551. doi: 10.1126/science.1074740. [PubMed] [Cross Ref]
36. Harrison J.C., Haber J.E. Surviving the breakup: The DNA damage checkpoint. Annu. Rev. Genet. 2006;40:209–235. doi: 10.1146/annurev.genet.40.051206.105231. [PubMed] [Cross Ref]
37. Harper J.W., Elledge S.J. The DNA damage response: Ten years after. Mol. Cell. 2007;28:739–745. doi: 10.1016/j.molcel.2007.11.015. [PubMed] [Cross Ref]
38. McKinnon P.J., Caldecott K.W. DNA strand break repair and human genetic disease. Annu. Rev. Genom. Hum. Genet. 2007;8:37–55. doi: 10.1146/annurev.genom.7.080505.115648. [PubMed] [Cross Ref]
39. Wilson D.M., Barsky D. The major human abasic endonuclease: Formation, consequences and repair of abasic lesions in DNA. Mutat. Res. 2001;485:283–307. doi: 10.1016/S0921-8777(01)00063-5. [PubMed] [Cross Ref]
40. Demple B., Sung J.-S. Molecular and biological roles of Ape1 protein in mammalian base excision repair. DNA Repair. 2005;4:1442–1449. doi: 10.1016/j.dnarep.2005.09.004. [PubMed] [Cross Ref]
41. Izumi T., Wiederhold L.R., Roy G., Roy R., Jaiswal A., Bhakat K.K., Mitra S., Hazra T.K. Mammalian DNA base excision repair proteins: Their interactions and role in repair of oxidative DNA damage. Toxicology. 2003;193:43–65. doi: 10.1016/S0300-483X(03)00289-0. [PubMed] [Cross Ref]
42. Dianov G.L., Sleeth K.M., Dianova I.I., Allinson S.L. Repair of abasic sites in DNA. Mutat. Res. 2003;531:157–163. doi: 10.1016/j.mrfmmm.2003.09.003. [PubMed] [Cross Ref]
43. Kim Y.-J., Wilson D.M. Overview of base excision repair biochemistry. Curr. Mol. Pharmacol. 2012;5:3–13. doi: 10.2174/1874467211205010003. [PMC free article] [PubMed] [Cross Ref]
44. Ménissier-de Murcia J., Molinete M., Gradwohl G., Simonin F., de Murcia G. Zinc-binding domain of poly(ADP-ribose)polymerase participates in the recognition of single strand breaks on DNA. J. Mol. Biol. 1989;210:229–233. doi: 10.1016/0022-2836(89)90302-1. [PubMed] [Cross Ref]
45. Khodyreva S.N., Prasad R., Ilina E.S., Sukhanova M.V., Kutuzov M.M., Liu Y., Hou E.W., Wilson S.H., Lavrik O.I. Apurinic/apyrimidinic (AP) site recognition by the 5′-dRP/AP lyase in poly(ADP-ribose) polymerase-1 (PARP-1) Proc. Natl. Acad. Sci. USA. 2010;107:22090–22095. doi: 10.1073/pnas.1009182107. [PubMed] [Cross Ref]
46. Fisher A.E.O., Hochegger H., Takeda S., Caldecott K.W. Poly(ADP-ribose) polymerase 1 accelerates single-strand break repair in concert with poly(ADP-ribose) glycohydrolase. Mol. Cell. Biol. 2007;27:5597–5605. doi: 10.1128/MCB.02248-06. [PMC free article] [PubMed] [Cross Ref]
47. Dianova I.I., Sleeth K.M., Allinson S.L., Parsons J.L., Breslin C., Caldecott K.W., Dianov G.L. XRCC1-DNA polymerase beta interaction is required for efficient base excision repair. Nucleic Acids Res. 2004;32:2550–2555. doi: 10.1093/nar/gkh567. [PMC free article] [PubMed] [Cross Ref]
48. Caldecott K.W., Aoufouchi S., Johnson P., Shall S. XRCC1 polypeptide interacts with DNA polymerase beta and possibly poly (ADP-ribose) polymerase, and DNA ligase III is a novel molecular “nick-sensor” in vitro. Nucleic Acids Res. 1996;24:4387–4394. doi: 10.1093/nar/24.22.4387. [PMC free article] [PubMed] [Cross Ref]
49. Masson M., Niedergang C., Schreiber V., Muller S., Menissier-de Murcia J., de Murcia G. XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage. Mol. Cell. Biol. 1998;18:3563–3571. doi: 10.1128/MCB.18.6.3563. [PMC free article] [PubMed] [Cross Ref]
50. Beneke S. Regulation of chromatin structure by poly(ADP-ribosyl)ation. Front. Genet. 2012;3:169. doi: 10.3389/fgene.2012.00169. [PMC free article] [PubMed] [Cross Ref]
51. Rouleau M., Patel A., Hendzel M.J., Kaufmann S.H., Poirier G.G. PARP inhibition: PARP1 and beyond. Nat. Rev. Cancer. 2010;10:293–301. doi: 10.1038/nrc2812. [PMC free article] [PubMed] [Cross Ref]
52. Schreiber V., Dantzer F., Ame J.-C., de Murcia G. Poly(ADP-ribose): Novel functions for an old molecule. Nat. Rev. Mol. Cell Biol. 2006;7:517–528. doi: 10.1038/nrm1963. [PubMed] [Cross Ref]
53. Marteijn J.A., Lans H., Vermeulen W., Hoeijmakers J.H.J. Understanding nucleotide excision repair and its roles in cancer and ageing. Nat. Rev. Mol. Cell Biol. 2014;15:465–481. doi: 10.1038/nrm3822. [PubMed] [Cross Ref]
54. Torgovnick A., Schumacher B. DNA repair mechanisms in cancer development and therapy. Front. Genet. 2015;6:157. doi: 10.3389/fgene.2015.00157. [PMC free article] [PubMed] [Cross Ref]
55. Hanawalt P.C., Spivak G. Transcription-coupled DNA repair: Two decades of progress and surprises. Nat. Rev. Mol. Cell Biol. 2008;9:958–970. doi: 10.1038/nrm2549. [PubMed] [Cross Ref]
56. Knoch J., Kamenisch Y., Kubisch C., Berneburg M. Rare hereditary diseases with defects in DNA-repair. Eur. J. Dermatol. 2012;22:443–455. [PubMed]
57. Guillotin D., Martin S.A. Exploiting DNA mismatch repair deficiency as a therapeutic strategy. Exp. Cell Res. 2014;329:110–115. doi: 10.1016/j.yexcr.2014.07.004. [PubMed] [Cross Ref]
58. Li G.-M. Mechanisms and functions of DNA mismatch repair. Cell Res. 2008;18:85–98. doi: 10.1038/cr.2007.115. [PubMed] [Cross Ref]
59. Modrich P., Lahue R. Mismatch repair in replication fidelity, genetic recombination, and cancer biology. Annu. Rev. Biochem. 1996;65:101–133. doi: 10.1146/annurev.bi.65.070196.000533. [PubMed] [Cross Ref]
60. Kunkel T.A., Erie D.A. DNA mismatch repair. Annu. Rev. Biochem. 2005;74:681–710. doi: 10.1146/annurev.biochem.74.082803.133243. [PubMed] [Cross Ref]
61. Jiricny J. The multifaceted mismatch-repair system. Nat. Rev. Mol. Cell Biol. 2006;7:335–346. doi: 10.1038/nrm1907. [PubMed] [Cross Ref]
62. Iyama T., Wilson D.M. DNA repair mechanisms in dividing and non-dividing cells. DNA Repair. 2013;12:620–636. doi: 10.1016/j.dnarep.2013.04.015. [PMC free article] [PubMed] [Cross Ref]
63. Arnheim N., Shibata D. DNA mismatch repair in mammals: Role in disease and meiosis. Curr. Opin. Genet. Dev. 1997;7:364–370. doi: 10.1016/S0959-437X(97)80150-5. [PubMed] [Cross Ref]
64. Peltomäki P. DNA mismatch repair and cancer. Mutat. Res. 2001;488:77–85. doi: 10.1016/S1383-5742(00)00058-2. [PubMed] [Cross Ref]
65. Ding Q., Reddy Y.V.R., Wang W., Woods T., Douglas P., Ramsden D.A., Lees-Miller S.P., Meek K. Autophosphorylation of the catalytic subunit of the DNA-dependent protein kinase is required for efficient end processing during DNA double-strand break repair. Mol. Cell. Biol. 2003;23:5836–5848. doi: 10.1128/MCB.23.16.5836-5848.2003. [PMC free article] [PubMed] [Cross Ref]
66. Helleday T., Lo J., van Gent D.C., Engelward B.P. DNA double-strand break repair: From mechanistic understanding to cancer treatment. DNA Repair. 2007;6:923–935. doi: 10.1016/j.dnarep.2007.02.006. [PubMed] [Cross Ref]
67. Deriano L., Roth D.B. Modernizing the nonhomologous end-joining repertoire: Alternative and classical NHEJ share the stage. Annu. Rev. Genet. 2013;47:433–455. doi: 10.1146/annurev-genet-110711-155540. [PubMed] [Cross Ref]
68. Nicolai S., Rossi A., di Daniele N., Melino G., Annicchiarico-Petruzzelli M., Raschellà G. DNA repair and aging: The impact of the p53 family. Aging. 2015;7:1050–1065. doi: 10.18632/aging.100858. [PMC free article] [PubMed] [Cross Ref]
69. Ahnesorg P., Smith P., Jackson S.P. XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell. 2006;124:301–313. doi: 10.1016/j.cell.2005.12.031. [PubMed] [Cross Ref]
70. Roy S., de Melo A.J., Xu Y., Tadi S.K., Négrel A., Hendrickson E., Modesti M., Meek K. XRCC4/XLF Interaction is variably required for DNA repair and is not required for ligase IV stimulation. Mol. Cell. Biol. 2015;35:3017–3028. doi: 10.1128/MCB.01503-14. [PMC free article] [PubMed] [Cross Ref]
71. Della-Maria J., Zhou Y., Tsai M.-S., Kuhnlein J., Carney J.P., Paull T.T., Tomkinson A.E. Human Mre11/human Rad50/Nbs1 and DNA ligase IIIalpha/XRCC1 protein complexes act together in an alternative nonhomologous end joining pathway. J. Biol. Chem. 2011;286:33845–33853. doi: 10.1074/jbc.M111.274159. [PMC free article] [PubMed] [Cross Ref]
72. Boboila C., Alt F.W., Schwer B. Classical and alternative end-joining pathways for repair of lymphocyte-specific and general DNA double-strand breaks. Adv. Immunol. 2012;116:1–49. [PubMed]
73. Metzger M.J., Stoddard B.L., Monnat R.J. PARP-mediated repair, homologous recombination, and back-up non-homologous end joining-like repair of single-strand nicks. DNA Repair. 2013;12:529–534. doi: 10.1016/j.dnarep.2013.04.004. [PMC free article] [PubMed] [Cross Ref]
74. Bunting S.F., Nussenzweig A. End-joining, translocations and cancer. Nat. Rev. Cancer. 2013;13:443–454. doi: 10.1038/nrc3537. [PubMed] [Cross Ref]
75. Audebert M., Salles B., Calsou P. Involvement of poly(ADP-ribose) polymerase-1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining. J. Biol. Chem. 2004;279:55117–55126. doi: 10.1074/jbc.M404524200. [PubMed] [Cross Ref]
76. Cuneo M.J., Gabel S.A., Krahn J.M., Ricker M.A., London R.E. The structural basis for partitioning of the XRCC1/DNA ligase III-α BRCT-mediated dimer complexes. Nucleic Acids Res. 2011;39:7816–7827. doi: 10.1093/nar/gkr419. [PMC free article] [PubMed] [Cross Ref]
77. Sfeir A., Symington L.S. Microhomology-mediated end joining: A back-up survival mechanism or dedicated pathway? Trends Biochem. Sci. 2015;40:701–714. doi: 10.1016/j.tibs.2015.08.006. [PMC free article] [PubMed] [Cross Ref]
78. Czornak K., Chughtai S., Chrzanowska K.H. Mystery of DNA repair: The role of the MRN complex and ATM kinase in DNA damage repair. J. Appl. Genet. 2008;49:383–396. doi: 10.1007/BF03195638. [PubMed] [Cross Ref]
79. Lamarche B.J., Orazio N.I., Weitzman M.D. The MRN complex in double-strand break repair and telomere maintenance. FEBS Lett. 2010;584:3682–3695. doi: 10.1016/j.febslet.2010.07.029. [PMC free article] [PubMed] [Cross Ref]
80. Aravind L., Makarova K.S., Koonin E.V. SURVEY AND SUMMARY: Holliday junction resolvases and related nucleases: Identification of new families, phyletic distribution and evolutionary trajectories. Nucleic Acids Res. 2000;28:3417–3432. doi: 10.1093/nar/28.18.3417. [PMC free article] [PubMed] [Cross Ref]
81. Wyatt H.D.M., West S.C. Holliday junction resolvases. Cold Spring Harb. Perspect. Biol. 2014;6:a023192. doi: 10.1101/cshperspect.a023192. [PMC free article] [PubMed] [Cross Ref]
82. Ip S.C.Y., Rass U., Blanco M.G., Flynn H.R., Skehel J.M., West S.C. Identification of Holliday junction resolvases from humans and yeast. Nature. 2008;456:357–361. doi: 10.1038/nature07470. [PubMed] [Cross Ref]
83. Bizard A.H., Hickson I.D. The dissolution of double Holliday junctions. Cold Spring Harb. Perspect. Biol. 2014;6:990 doi: 10.1101/cshperspect.a016477. [PMC free article] [PubMed] [Cross Ref]
84. Swuec P., Costa A. Molecular mechanism of double Holliday junction dissolution. Cell Biosci. 2014;4:36. doi: 10.1186/2045-3701-4-36. [PMC free article] [PubMed] [Cross Ref]
85. Bocquet N., Bizard A.H., Abdulrahman W., Larsen N.B., Faty M., Cavadini S., Bunker R.D., Kowalczykowski S.C., Cejka P., Hickson I.D., et al. Structural and mechanistic insight into Holliday-junction dissolution by topoisomerase IIIα and RMI1. Nat. Struct. Mol. Biol. 2014;21:261–268. doi: 10.1038/nsmb.2775. [PMC free article] [PubMed] [Cross Ref]
86. San Filippo J., Sung P., Klein H. Mechanism of eukaryotic homologous recombination. Annu. Rev. Biochem. 2008;77:229–257. doi: 10.1146/annurev.biochem.77.061306.125255. [PubMed] [Cross Ref]
87. Moynahan M.E., Jasin M. Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat. Rev. Mol. Cell Biol. 2010;11:196–207. doi: 10.1038/nrm2851. [PMC free article] [PubMed] [Cross Ref]
88. Symington L.S., Gautier J. Double-strand break end resection and repair pathway choice. Annu. Rev. Genet. 2011;45:247–271. doi: 10.1146/annurev-genet-110410-132435. [PubMed] [Cross Ref]
89. Bakr A., Oing C., Köcher S., Borgmann K., Dornreiter I., Petersen C., Dikomey E., Mansour W.Y. Involvement of ATM in homologous recombination after end resection and RAD51 nucleofilament formation. Nucleic Acids Res. 2015;43:3154–3166. doi: 10.1093/nar/gkv160. [PMC free article] [PubMed] [Cross Ref]
90. Dahm-Daphi J., Hubbe P., Horvath F., El-Awady R.A., Bouffard K.E., Powell S.N., Willers H. Nonhomologous end-joining of site-specific but not of radiation-induced DNA double-strand breaks is reduced in the presence of wild-type p53. Oncogene. 2005;24:1663–1672. doi: 10.1038/sj.onc.1208396. [PubMed] [Cross Ref]
91. Menon V., Povirk L. Involvement of p53 in the repair of DNA double strand breaks: Multifaceted roles of p53 in homologous recombination repair (HRR) and non-homologous end joining (NHEJ) Subcell. Biochem. 2014;85:321–336. [PMC free article] [PubMed]
92. Panier S., Boulton S.J. Double-strand break repair: 53BP1 comes into focus. Nat. Rev. Mol. Cell Biol. 2014;15:7–18. doi: 10.1038/nrm3719. [PubMed] [Cross Ref]
93. Bau D.-T., Mau Y.-C., Shen C.-Y. The role of BRCA1 in non-homologous end-joining. Cancer Lett. 2006;240:1–8. doi: 10.1016/j.canlet.2005.08.003. [PubMed] [Cross Ref]
94. Welcsh P.L., King M.C. BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. Hum. Mol. Genet. 2001;10:705–713. doi: 10.1093/hmg/10.7.705. [PubMed] [Cross Ref]
95. Haupt S., Raghu D., Haupt Y. Mutant p53 drives cancer by subverting multiple tumor suppression pathways. Front. Oncol. 2016;6:12. doi: 10.3389/fonc.2016.00012. [PMC free article] [PubMed] [Cross Ref]
96. Guirouilh-Barbat J., Lambert S., Bertrand P., Lopez B.S. Is homologous recombination really an error-free process? Front. Genet. 2014;5 doi: 10.3389/fgene.2014.00175. [PMC free article] [PubMed] [Cross Ref]
97. Sharma S., Javadekar S.M., Pandey M., Srivastava M., Kumari R., Raghavan S.C. Homology and enzymatic requirements of microhomology-dependent alternative end joining. Cell Death Dis. 2015;6:e1697. doi: 10.1038/cddis.2015.58. [PMC free article] [PubMed] [Cross Ref]
98. Aparicio T., Baer R., Gautier J. DNA double-strand break repair pathway choice and cancer. DNA Repair. 2014;19:169–175. doi: 10.1016/j.dnarep.2014.03.014. [PMC free article] [PubMed] [Cross Ref]
99. Sinha S., Villarreal D., Shim E.Y., Lee S.E. Risky business: Microhomology-mediated end joining. Mutat. Res. 2016 doi: 10.1016/j.mrfmmm.2015.12.005. [PMC free article] [PubMed] [Cross Ref]
100. Kent T., Chandramouly G., McDevitt S.M., Ozdemir A.Y., Pomerantz R.T. Mechanism of microhomology-mediated end-joining promoted by human DNA polymerase θ Nat. Struct. Mol. Biol. 2015;22:230–237. doi: 10.1038/nsmb.2961. [PMC free article] [PubMed] [Cross Ref]
101. Lemée F., Bergoglio V., Fernandez-Vidal A., Machado-Silva A., Pillaire M.-J., Bieth A., Gentil C., Baker L., Martin A.-L., Leduc C., et al. DNA polymerase theta up-regulation is associated with poor survival in breast cancer, perturbs DNA replication, and promotes genetic instability. Proc. Natl. Acad. Sci. USA. 2010;107:13390–13395. doi: 10.1073/pnas.0910759107. [PubMed] [Cross Ref]
102. Higgins G.S., Harris A.L., Prevo R., Helleday T., McKenna W.G., Buffa F.M. Overexpression of POLQ confers a poor prognosis in early breast cancer patients. Oncotarget. 2010;1:175–184. doi: 10.18632/oncotarget.124. [PMC free article] [PubMed] [Cross Ref]
103. Lee S.D., Shroyer K.R., Markham N.E., Cool C.D., Voelkel N.F., Tuder R.M. Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J. Clin. Investig. 1998;101:927–934. doi: 10.1172/JCI1910. [PMC free article] [PubMed] [Cross Ref]
104. Tuder R.M., Radisavljevic Z., Shroyer K.R., Polak J.M., Voelkel N.F. Monoclonal endothelial cells in appetite suppressant-associated pulmonary hypertension. Am. J. Respir. Crit. Care Med. 1998;158:1999–2001. doi: 10.1164/ajrccm.158.6.9805002. [PubMed] [Cross Ref]
105. Yeager M.E., Halley G.R., Golpon H.A., Voelkel N.F., Tuder R.M. Microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in primary pulmonary hypertension. Circ. Res. 2001;88:E2–E11. doi: 10.1161/01.RES.88.1.e2. [PubMed] [Cross Ref]
106. Aldred M.A., Comhair S.A., Varella-Garcia M., Asosingh K., Xu W., Noon G.P., Thistlethwaite P.A., Tuder R.M., Erzurum S.C., Geraci M.W., et al. Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 2010;182:1153–1160. doi: 10.1164/rccm.201003-0491OC. [PMC free article] [PubMed] [Cross Ref]
107. Federici C., Drake K.M., Rigelsky C.M., McNelly L.N., Meade S.L., Comhair S.A.A., Erzurum S.C., Aldred M.A. Increased Mutagen Sensitivity and DNA Damage in Pulmonary Arterial Hypertension. Am. J. Respir. Crit. Care Med. 2015;192:219–228. doi: 10.1164/rccm.201411-2128OC. [PMC free article] [PubMed] [Cross Ref]
108. Simonneau G., Gatzoulis M.A., Adatia I., Celermajer D., Denton C., Ghofrani A., Gomez Sanchez M.A., Krishna Kumar R., Landzberg M., Machado R.F., et al. Updated clinical classification of pulmonary hypertension. J. Am. Coll. Cardiol. 2013;62:D34–D41. doi: 10.1016/j.jacc.2013.10.029. [PubMed] [Cross Ref]
109. Sanchez O., Sitbon O., Jaïs X., Simonneau G., Humbert M. Immunosuppressive therapy in connective tissue diseases-associated pulmonary arterial hypertension. Chest. 2006;130:182–189. doi: 10.1378/chest.130.1.182. [PubMed] [Cross Ref]
110. Karmochkine M., Wechsler B., Godeau P., Brenot F., Jagot J.L., Simonneau G. Improvement of severe pulmonary hypertension in a patient with SLE. Ann. Rheum. Dis. 1996;55:561–562. doi: 10.1136/ard.55.8.561. [PMC free article] [PubMed] [Cross Ref]
111. Meloche J., Renard S., Provencher S., Bonnet S. Anti-inflammatory and immunosuppressive agents in PAH. Handb. Exp. Pharmacol. 2013;218:437–476. [PubMed]
112. Jouve P., Humbert M., Chauveheid M.-P., Jaïs X., Papo T. POEMS syndrome-related pulmonary hypertension is steroid-responsive. Respir. Med. 2007;101:353–355. doi: 10.1016/j.rmed.2006.04.026. [PubMed] [Cross Ref]
113. Dorfmüller P., Perros F., Balabanian K., Humbert M. Inflammation in pulmonary arterial hypertension. Eur. Respir. J. 2003;22:358–363. doi: 10.1183/09031936.03.00038903. [PubMed] [Cross Ref]
114. Perros F., Dorfmüller P., Montani D., Hammad H., Waelput W., Girerd B., Raymond N., Mercier O., Mussot S., Cohen-Kaminsky S., et al. Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 2012;185:311–321. doi: 10.1164/rccm.201105-0927OC. [PubMed] [Cross Ref]
115. Cohen-Kaminsky S., Ranchoux B., Perros F. CXCL13 in tertiary lymphoid tissues: Sites of production are different from sites of functional localization. Am. J. Respir. Crit. Care Med. 2014;189:369–370. doi: 10.1164/rccm.201307-1389LE. [PubMed] [Cross Ref]
116. Price L.C., Wort S.J., Perros F., Dorfmüller P., Huertas A., Montani D., Cohen-Kaminsky S., Humbert M. Inflammation in pulmonary arterial hypertension. Chest. 2012;141:210–221. doi: 10.1378/chest.11-0793. [PubMed] [Cross Ref]
117. Perros F., Cohen-Kaminsky S., Gambaryan N., Girerd B., Raymond N., Klingelschmitt I., Huertas A., Mercier O., Fadel E., Simonneau G., et al. Cytotoxic cells and granulysin in pulmonary arterial hypertension and pulmonary veno-occlusive disease. Am. J. Respir. Crit. Care Med. 2013;187:189–196. doi: 10.1164/rccm.201208-1364OC. [PubMed] [Cross Ref]
118. Montani D., Perros F., Gambaryan N., Girerd B., Dorfmuller P., Price L.C., Huertas A., Hammad H., Lambrecht B., Simonneau G., et al. C-Kit-positive cells accumulate in remodeled vessels of idiopathic pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 2011;184:116–123. doi: 10.1164/rccm.201006-0905OC. [PubMed] [Cross Ref]
119. Perros F., Dorfmüller P., Souza R., Durand-Gasselin I., Mussot S., Mazmanian M., Hervé P., Emilie D., Simonneau G., Humbert M. Dendritic cell recruitment in lesions of human and experimental pulmonary hypertension. Eur. Respir. J. 2007;29:462–468. doi: 10.1183/09031936.00094706. [PubMed] [Cross Ref]
120. Humbert M., Monti G., Brenot F., Sitbon O., Portier A., Grangeot-Keros L., Duroux P., Galanaud P., Simonneau G., Emilie D. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am. J. Respir. Crit. Care Med. 1995;151:1628–1631. doi: 10.1164/ajrccm.151.5.7735624. [PubMed] [Cross Ref]
121. Soon E., Holmes A.M., Treacy C.M., Doughty N.J., Southgate L., Machado R.D., Trembath R.C., Jennings S., Barker L., Nicklin P., et al. Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation. 2010;122:920–927. doi: 10.1161/CIRCULATIONAHA.109.933762. [PubMed] [Cross Ref]
122. Hautefort A., Girerd B., Montani D., Cohen-Kaminsky S., Price L., Lambrecht B.N., Humbert M., Perros F. T-helper 17 cell polarization in pulmonary arterial hypertension. Chest. 2015;147:1610–1620. doi: 10.1378/chest.14-1678. [PubMed] [Cross Ref]
123. Itoh T., Nagaya N., Ishibashi-Ueda H., Kyotani S., Oya H., Sakamaki F., Kimura H., Nakanishi N. Increased plasma monocyte chemoattractant protein-1 level in idiopathic pulmonary arterial hypertension. Respirology. 2006;11:158–163. doi: 10.1111/j.1440-1843.2006.00821.x. [PubMed] [Cross Ref]
124. Golembeski S.M., West J., Tada Y., Fagan K.A. Interleukin-6 causes mild pulmonary hypertension and augments hypoxia-induced pulmonary hypertension in mice. Chest. 2005;128:572S–573S. doi: 10.1378/chest.128.6_suppl.572S-a. [PubMed] [Cross Ref]
125. Miyata M., Sakuma F., Yoshimura A., Ishikawa H., Nishimaki T., Kasukawa R. Pulmonary hypertension in rats. 2. Role of interleukin-6. Int. Arch. Allergy Immunol. 1995;108:287–291. doi: 10.1159/000237166. [PubMed] [Cross Ref]
126. Steiner M.K., Syrkina O.L., Kolliputi N., Mark E.J., Hales C.A., Waxman A.B. Interleukin-6 overexpression induces pulmonary hypertension. Circ. Res. 2009;104:236–244. doi: 10.1161/CIRCRESAHA.108.182014. [PubMed] [Cross Ref]
127. Savale L., Tu L., Rideau D., Izziki M., Maitre B., Adnot S., Eddahibi S. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respir. Res. 2009;10:6. doi: 10.1186/1465-9921-10-6. [PMC free article] [PubMed] [Cross Ref]
128. Meira L.B., Bugni J.M., Green S.L., Lee C.-W., Pang B., Borenshtein D., Rickman B.H., Rogers A.B., Moroski-Erkul C.A., McFaline J.L., et al. DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice. J. Clin. Investig. 2008;118:2516–2525. doi: 10.1172/JCI35073. [PubMed] [Cross Ref]
129. Wheelhouse N.M., Chan Y.-S., Gillies S.E., Caldwell H., Ross J.A., Harrison D.J., Prost S. TNF-α induced DNA damage in primary murine hepatocytes. Int. J. Mol. Med. 2003;12:889–894. doi: 10.3892/ijmm.12.6.889. [PubMed] [Cross Ref]
130. Suematsu N., Tsutsui H., Wen J., Kang D., Ikeuchi M., Ide T., Hayashidani S., Shiomi T., Kubota T., Hamasaki N., et al. Oxidative stress mediates tumor necrosis factor-alpha-induced mitochondrial DNA damage and dysfunction in cardiac myocytes. Circulation. 2003;107:1418–1423. doi: 10.1161/01.CIR.0000055318.09997.1F. [PubMed] [Cross Ref]
131. Poltz R., Naumann M. Dynamics of p53 and NF-κB regulation in response to DNA damage and identification of target proteins suitable for therapeutic intervention. BMC Syst. Biol. 2012;6:125. doi: 10.1186/1752-0509-6-125. [PMC free article] [PubMed] [Cross Ref]
132. Pikarsky E., Porat R.M., Stein I., Abramovitch R., Amit S., Kasem S., Gutkovich-Pyest E., Urieli-Shoval S., Galun E., Ben-Neriah Y. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature. 2004;431:461–466. doi: 10.1038/nature02924. [PubMed] [Cross Ref]
133. Kidane D., Chae W.J., Czochor J., Eckert K.A., Glazer P.M., Bothwell A.L.M., Sweasy J.B. Interplay between DNA repair and inflammation, and the link to cancer. Crit. Rev. Biochem. Mol. Biol. 2014;49:116–139. doi: 10.3109/10409238.2013.875514. [PMC free article] [PubMed] [Cross Ref]
134. Hussain S.P., Harris C.C. Inflammation and cancer: An ancient link with novel potentials. Int. J. Cancer. 2007;121:2373–2380. doi: 10.1002/ijc.23173. [PubMed] [Cross Ref]
135. Schetter A.J., Heegaard N.H.H., Harris C.C. Inflammation and cancer: Interweaving microRNA, free radical, cytokine and p53 pathways. Carcinogenesis. 2010;31:37–49. doi: 10.1093/carcin/bgp272. [PMC free article] [PubMed] [Cross Ref]
136. Pálmai-Pallag T., Bachrati C.Z. Inflammation-induced DNA damage and damage-induced inflammation: A vicious cycle. Microbes Infect. Inst. Pasteur. 2014;16:822–832. doi: 10.1016/j.micinf.2014.10.001. [PubMed] [Cross Ref]
137. Olivieri F., Albertini M.C., Orciani M., Ceka A., Cricca M., Procopio A.D., Bonafè M. DNA damage response (DDR) and senescence: Shuttled inflamma-miRNAs on the stage of inflamm-aging. Oncotarget. 2015;6:35509–35521. [PMC free article] [PubMed]
138. Yun U.J., Park S.E., Jo Y.S., Kim J., Shin D.Y. DNA damage induces the IL-6/STAT3 signaling pathway, which has anti-senescence and growth-promoting functions in human tumors. Cancer Lett. 2012;323:155–160. doi: 10.1016/j.canlet.2012.04.003. [PubMed] [Cross Ref]
139. Grivennikov S., Karin E., Terzic J., Mucida D., Yu G.-Y., Vallabhapurapu S., Scheller J., Rose-John S., Cheroutre H., Eckmann L., et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 2009;15:103–113. doi: 10.1016/j.ccr.2009.01.001. [PMC free article] [PubMed] [Cross Ref]
140. Bromberg J., Wang T.C. Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell. 2009;15:79–80. doi: 10.1016/j.ccr.2009.01.009. [PMC free article] [PubMed] [Cross Ref]
141. Morrell N.W. Pulmonary hypertension due to BMPR2 mutation: A new paradigm for tissue remodeling? Proc. Am. Thorac. Soc. 2006;3:680–686. doi: 10.1513/pats.200605-118SF. [PubMed] [Cross Ref]
142. Hagen M., Fagan K., Steudel W., Carr M., Lane K., Rodman D.M., West J. Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle. Am. J. Physiol. Lung Cell. Mol. Physiol. 2007;292:L1473–L1479. doi: 10.1152/ajplung.00197.2006. [PubMed] [Cross Ref]
143. Perros F., Bonnet S. Bone morphogenetic protein receptor type II and inflammation are bringing old concepts into the new pulmonary arterial hypertension world. Am. J. Respir. Crit. Care Med. 2015;192:777–779. doi: 10.1164/rccm.201506-1115ED. [PubMed] [Cross Ref]
144. Soon E., Crosby A., Southwood M., Yang P., Tajsic T., Toshner M., Appleby S., Shanahan C.M., Bloch K.D., Pepke-Zaba J., et al. Bone morphogenetic protein receptor type II deficiency and increased inflammatory cytokine production. A gateway to pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 2015;192:859–872. doi: 10.1164/rccm.201408-1509OC. [PMC free article] [PubMed] [Cross Ref]
145. Paulin R., Meloche J., Bonnet S. STAT3 signaling in pulmonary arterial hypertension. JAK-STAT. 2012;1:223–233. doi: 10.4161/jkst.22366. [PMC free article] [PubMed] [Cross Ref]
146. Perros F., Montani D., Dorfmüller P., Durand-Gasselin I., Tcherakian C., Le Pavec J., Mazmanian M., Fadel E., Mussot S., Mercier O., et al. Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 2008;178:81–88. doi: 10.1164/rccm.200707-1037OC. [PubMed] [Cross Ref]
147. Aggarwal S., Gross C.M., Sharma S., Fineman J.R., Black S.M. Reactive oxygen species in pulmonary vascular remodeling. Compr. Physiol. 2013;3:1011–1034. [PMC free article] [PubMed]
148. Bowers R., Cool C., Murphy R.C., Tuder R.M., Hopken M.W., Flores S.C., Voelkel N.F. Oxidative stress in severe pulmonary hypertension. Am. J. Respir. Crit. Care Med. 2004;169:764–769. doi: 10.1164/rccm.200301-147OC. [PubMed] [Cross Ref]
149. Demarco V.G., Whaley-Connell A.T., Sowers J.R., Habibi J., Dellsperger K.C. Contribution of oxidative stress to pulmonary arterial hypertension. World J. Cardiol. 2010;2:316–324. doi: 10.4330/wjc.v2.i10.316. [PMC free article] [PubMed] [Cross Ref]
150. Dorfmüller P., Chaumais M.-C., Giannakouli M., Durand-Gasselin I., Raymond N., Fadel E., Mercier O., Charlotte F., Montani D., Simonneau G., et al. Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension. Respir. Res. 2011;12:119. doi: 10.1186/1465-9921-12-119. [PMC free article] [PubMed] [Cross Ref]
151. Black S.M., DeVol J.M., Wedgwood S. Regulation of fibroblast growth factor-2 expression in pulmonary arterial smooth muscle cells involves increased reactive oxygen species generation. Am. J. Physiol. Cell Physiol. 2008;294:C345–C354. doi: 10.1152/ajpcell.00216.2007. [PubMed] [Cross Ref]
152. Montisano D.F., Mann T., Spragg R.G. H2O2 increases expression of pulmonary artery endothelial cell platelet-derived growth factor mRNA. J. Appl. Physiol. 1992;73:2255–2262. [PubMed]
153. Wedgwood S., Dettman R.W., Black S.M. ET-1 stimulates pulmonary arterial smooth muscle cell proliferation via induction of reactive oxygen species. Am. J. Physiol. Lung Cell. Mol. Physiol. 2001;281:L1058–1067. [PubMed]
154. Block K., Gorin Y., Hoover P., Williams P., Chelmicki T., Clark R.A., Yoneda T., Abboud H.E. NAD(P)H oxidases regulate HIF-2alpha protein expression. J. Biol. Chem. 2007;282:8019–8026. doi: 10.1074/jbc.M611569200. [PubMed] [Cross Ref]
155. Chandel N.S., McClintock D.S., Feliciano C.E., Wood T.M., Melendez J.A., Rodriguez A.M., Schumacker P.T. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1α during hypoxia A MECHANISM OF O2 SENSING. J. Biol. Chem. 2000;275:25130–25138. doi: 10.1074/jbc.M001914200. [PubMed] [Cross Ref]
156. Gale D.P., Harten S.K., Reid C.D.L., Tuddenham E.G.D., Maxwell P.H. Autosomal dominant erythrocytosis and pulmonary arterial hypertension associated with an activating HIF2α mutation. Blood. 2008;112:919–921. doi: 10.1182/blood-2008-04-153718. [PubMed] [Cross Ref]
157. Brusselmans K., Compernolle V., Tjwa M., Wiesener M.S., Maxwell P.H., Collen D., Carmeliet P. Heterozygous deficiency of hypoxia-inducible factor–2α protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia. J. Clin. Investig. 2003;111:1519–1527. doi: 10.1172/JCI15496. [PMC free article] [PubMed] [Cross Ref]
158. Cheng T.H., Shih N.L., Chen S.Y., Loh S.H., Cheng P.Y., Tsai C.S., Liu S.H., Wang D.L., Chen J.J. Reactive oxygen species mediate cyclic strain-induced endothelin-1 gene expression via Ras/Raf/extracellular signal-regulated kinase pathway in endothelial cells. J. Mol. Cell. Cardiol. 2001;33:1805–1814. doi: 10.1006/jmcc.2001.1444. [PubMed] [Cross Ref]
159. Tate R.M., Morris H.G., Schroeder W.R., Repine J.E. Oxygen metabolites stimulate thromboxane production and vasoconstriction in isolated saline-perfused rabbit lungs. J. Clin. Investig. 1984;74:608–613. doi: 10.1172/JCI111458. [PMC free article] [PubMed] [Cross Ref]
160. Lee D.S., McCallum E.A., Olson D.M. Effects of reactive oxygen species on prostacyclin production in perinatal rat lung cells. J. Appl. Physiol. 1989;66:1321–1327. [PubMed]
161. Brito R., Castillo G., González J., Valls N., Rodrigo R. Oxidative stress in hypertension: Mechanisms and therapeutic opportunities. Exp. Clin. Endocrinol. Diabetes. 2015;123:325–335. doi: 10.1055/s-0035-1548765. [PubMed] [Cross Ref]
162. Weissmann N., Winterhalder S., Nollen M., Voswinckel R., Quanz K., Ghofrani H.A., Schermuly R.T., Seeger W., Grimminger F. NO and reactive oxygen species are involved in biphasic hypoxic vasoconstriction of isolated rabbit lungs. Am. J. Physiol. Lung Cell. Mol. Physiol. 2001;280:L638–L645. [PubMed]
163. Waypa G.B., Marks J.D., Mack M.M., Boriboun C., Mungai P.T., Schumacker P.T. Mitochondrial Reactive oxygen species trigger calcium increases during hypoxia in pulmonary arterial myocytes. Circ. Res. 2002;91:719–726. doi: 10.1161/01.RES.0000036751.04896.F1. [PubMed] [Cross Ref]
164. Hoshikawa Y., Ono S., Suzuki S., Tanita T., Chida M., Song C., Noda M., Tabata T., Voelkel N.F., Fujimura S. Generation of oxidative stress contributes to the development of pulmonary hypertension induced by hypoxia. J. Appl. Physiol. 2001;90:1299–1306. [PubMed]
165. Jankov R.P., Kantores C., Pan J., Belik J. Contribution of xanthine oxidase-derived superoxide to chronic hypoxic pulmonary hypertension in neonatal rats. Am. J. Physiol. 2008;294:L233–L245. doi: 10.1152/ajplung.00166.2007. [PubMed] [Cross Ref]
166. Rafikova O., Rafikov R., Kangath A., Qu N., Aggarwal S., Sharma S., Desai J., Fields T., Ludewig B., Yuan J.X.-Y., et al. Redox regulation of epidermal growth factor receptor signaling during the development of pulmonary hypertension. Free Radic. Biol. Med. 2016 doi: 10.1016/j.freeradbiomed.2016.02.029. [PubMed] [Cross Ref]
167. Rawat D.K., Alzoubi A., Gupte R., Chettimada S., Watanabe M., Kahn A.G., Okada T., McMurtry I.F., Gupte S.A. Increased reactive oxygen species, metabolic maladaptation, and autophagy contribute to pulmonary arterial hypertension-induced ventricular hypertrophy and diastolic heart failure. Hypertension. 2014;64:1266–1274. doi: 10.1161/HYPERTENSIONAHA.114.03261. [PubMed] [Cross Ref]
168. Liu J.Q., Zelko I.N., Erbynn E.M., Sham J.S.K., Folz R.J. Hypoxic pulmonary hypertension: Role of superoxide and NADPH oxidase (gp91phox) Am. J. Physiol. Lung Cell. Mol. Physiol. 2006;290:L2–L10. doi: 10.1152/ajplung.00135.2005. [PubMed] [Cross Ref]
169. Matsui H., Shimosawa T., Itakura K., Guanqun X., Ando K., Fujita T. Adrenomedullin can protect against pulmonary vascular remodeling induced by hypoxia. Circulation. 2004;109:2246–2251. doi: 10.1161/01.CIR.0000127950.13380.FD. [PubMed] [Cross Ref]
170. Liu M., Wang Y., Zheng L., Zheng W., Dong K., Chen S., Zhang B., Li Z. Fasudil reversed MCT-induced and chronic hypoxia-induced pulmonary hypertension by attenuating oxidative stress and inhibiting the expression of Trx1 and HIF-1α Respir. Physiol. Neurobiol. 2014;201:38–46. doi: 10.1016/j.resp.2014.06.001. [PubMed] [Cross Ref]
171. Zhang B., Niu W., Xu D., Li Y., Liu M., Wang Y., Luo Y., Zhao P., Liu Y., Dong M., et al. Oxymatrine prevents hypoxia- and monocrotaline-induced pulmonary hypertension in rats. Free Radic. Biol. Med. 2014;69:198–207. doi: 10.1016/j.freeradbiomed.2014.01.013. [PubMed] [Cross Ref]
172. Chaumais M.-C., Ranchoux B., Montani D., Dorfmüller P., Tu L., Lecerf F., Raymond N., Guignabert C., Price L., Simonneau G., et al. N-acetylcysteine improves established monocrotaline-induced pulmonary hypertension in rats. Respir. Res. 2014;15:65. doi: 10.1186/1465-9921-15-65. [PMC free article] [PubMed] [Cross Ref]
173. Mittal M., Roth M., König P., Hofmann S., Dony E., Goyal P., Selbitz A.-C., Schermuly R.T., Ghofrani H.A., Kwapiszewska G., et al. Hypoxia-dependent regulation of nonphagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature. Circ. Res. 2007;101:258–267. doi: 10.1161/CIRCRESAHA.107.148015. [PubMed] [Cross Ref]
174. Babior B.M. The NADPH oxidase of endothelial cells. IUBMB Life. 2000;50:267–269. doi: 10.1080/15216540051080976. [PubMed] [Cross Ref]
175. Vignais P.V. The superoxide-generating NADPH oxidase: Structural aspects and activation mechanism. Cell. Mol. Life Sci. 2002;59:1428–1459. doi: 10.1007/s00018-002-8520-9. [PubMed] [Cross Ref]
176. Fresquet F., Pourageaud F., Leblais V., Brandes R.P., Savineau J.-P., Marthan R., Muller B. Role of reactive oxygen species and gp91phox in endothelial dysfunction of pulmonary arteries induced by chronic hypoxia. Br. J. Pharmacol. 2006;148:714–723. doi: 10.1038/sj.bjp.0706779. [PMC free article] [PubMed] [Cross Ref]
177. Paravicini T.M., Gulluyan L.M., Dusting G.J., Drummond G.R. Increased NADPH oxidase activity, gp91phox expression, and endothelium-dependent vasorelaxation during neointima formation in rabbits. Circ. Res. 2002;91:54–61. doi: 10.1161/01.RES.0000024106.81401.95. [PubMed] [Cross Ref]
178. Li S., Tabar S.S., Malec V., Eul B.G., Klepetko W., Weissmann N., Grimminger F., Seeger W., Rose F., Hänze J. NOX4 regulates ROS levels under normoxic and hypoxic conditions, triggers proliferation, and inhibits apoptosis in pulmonary artery adventitial fibroblasts. Antioxid. Redox Signal. 2008;10:1687–1698. doi: 10.1089/ars.2008.2035. [PubMed] [Cross Ref]
179. Sturrock A., Cahill B., Norman K., Huecksteadt T.P., Hill K., Sanders K., Karwande S.V., Stringham J.C., Bull D.A., Gleich M., et al. Transforming growth factor-beta1 induces Nox4 NAD(P)H oxidase and reactive oxygen species-dependent proliferation in human pulmonary artery smooth muscle cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 2006;290:L661–L673. doi: 10.1152/ajplung.00269.2005. [PubMed] [Cross Ref]
180. Selimovic N., Bergh C.-H., Andersson B., Sakiniene E., Carlsten H., Rundqvist B. Growth factors and interleukin-6 across the lung circulation in pulmonary hypertension. Eur. Respir. J. 2009;34:662–668. doi: 10.1183/09031936.00174908. [PubMed] [Cross Ref]
181. Landmesser U., Dikalov S., Price S.R., McCann L., Fukai T., Holland S.M., Mitch W.E., Harrison D.G. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J. Clin. Investig. 2003;111:1201–1209. doi: 10.1172/JCI200314172. [PMC free article] [PubMed] [Cross Ref]
182. Morris C.R., Kato G.J., Poljakovic M., Wang X., Blackwelder W.C., Sachdev V., Hazen S.L., Vichinsky E.P., Morris S.M., Gladwin M.T. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA. 2005;294:81–90. doi: 10.1001/jama.294.1.81. [PMC free article] [PubMed] [Cross Ref]
183. Pullamsetti S., Kiss L., Ghofrani H.A., Voswinckel R., Haredza P., Klepetko W., Aigner C., Fink L., Muyal J.P., Weissmann N., et al. Increased levels and reduced catabolism of asymmetric and symmetric dimethylarginines in pulmonary hypertension. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2005;19:1175–1177. doi: 10.1186/1471-2210-5-S1-P45. [PubMed] [Cross Ref]
184. Iannone L., Zhao L., Dubois O., Duluc L., Rhodes C.J., Wharton J., Wilkins M.R., Leiper J., Wojciak-Stothard B. miR-21/DDAH1 pathway regulates pulmonary vascular responses to hypoxia. Biochem. J. 2014;462:103–112. doi: 10.1042/BJ20140486. [PubMed] [Cross Ref]
185. Li X.-H., Peng J., Tan N., Wu W.-H., Li T.-T., Shi R.-Z., Li Y.-J. Involvement of asymmetric dimethylarginine and Rho kinase in the vascular remodeling in monocrotaline-induced pulmonary hypertension. Vascul. Pharmacol. 2010;53:223–229. doi: 10.1016/j.vph.2010.09.002. [PubMed] [Cross Ref]
186. Archer S.L., Marsboom G., Kim G.H., Zhang H.J., Toth P.T., Svensson E.C., Dyck J.R.B., Gomberg-Maitland M., Thébaud B., Husain A.N., et al. Epigenetic attenuation of mitochondrial superoxide dismutase 2 (SOD2) in pulmonary arterial hypertension. Circulation. 2010;121:2661–2671. doi: 10.1161/CIRCULATIONAHA.109.916098. [PMC free article] [PubMed] [Cross Ref]
187. Reis G.S., Augusto V.S., Silveira A.P.C., Jordão A.A., Baddini-Martinez J., Poli Neto O., Rodrigues A.J., Evora P.R.B. Oxidative-stress biomarkers in patients with pulmonary hypertension. Pulm. Circ. 2013;3:856–861. doi: 10.1086/674764. [PMC free article] [PubMed] [Cross Ref]
188. Cracowski J.L., Cracowski C., Bessard G., Pepin J.L., Bessard J., Schwebel C., Stanke-Labesque F., Pison C. Increased lipid peroxidation in patients with pulmonary hypertension. Am. J. Respir. Crit. Care Med. 2001;164:1038–1042. doi: 10.1164/ajrccm.164.6.2104033. [PubMed] [Cross Ref]
189. Wong C.-M., Bansal G., Pavlickova L., Marcocci L., Suzuki Y.J. Reactive oxygen species and antioxidants in pulmonary hypertension. Antioxid. Redox Signal. 2013;18:1789–1796. doi: 10.1089/ars.2012.4568. [PMC free article] [PubMed] [Cross Ref]
190. Tabima D.M., Frizzell S., Gladwin M.T. Reactive oxygen and nitrogen species in pulmonary hypertension. Free Radic. Biol. Med. 2012;52:1970–1986. doi: 10.1016/j.freeradbiomed.2012.02.041. [PMC free article] [PubMed] [Cross Ref]
191. Crosswhite P., Sun Z. Nitric oxide, oxidative stress and inflammation in pulmonary arterial hypertension. J. Hypertens. 2010;28:201–212. doi: 10.1097/HJH.0b013e328332bcdb. [PMC free article] [PubMed] [Cross Ref]
192. Yasui M., Kanemaru Y., Kamoshita N., Suzuki T., Arakawa T., Honma M. Tracing the fates of site-specifically introduced DNA adducts in the human genome. DNA Repair. 2014;15:11–20. doi: 10.1016/j.dnarep.2014.01.003. [PubMed] [Cross Ref]
193. Martinez G.R., Loureiro A.P.M., Marques S.A., Miyamoto S., Yamaguchi L.F., Onuki J., Almeida E.A., Garcia C.C.M., Barbosa L.F., Medeiros M.H.G., et al. Oxidative and alkylating damage in DNA. Mutat. Res. 2003;544:115–127. doi: 10.1016/j.mrrev.2003.05.005. [PubMed] [Cross Ref]
194. Klaunig J.E., Kamendulis L.M., Hocevar B.A. Oxidative stress and oxidative damage in carcinogenesis. Toxicol. Pathol. 2010;38:96–109. doi: 10.1177/0192623309356453. [PubMed] [Cross Ref]
195. Gurtner H.P. Aminorex and pulmonary hypertension. A review. Cor et Vasa. 1985;27:160–171. [PubMed]
196. Simonneau G., Fartoukh M., Sitbon O., Humbert M., Jagot J.L., Hervé P. Primary pulmonary hypertension associated with the use of fenfluramine derivatives. Chest. 1998;114:195S–199S. doi: 10.1378/chest.114.3_Supplement.195S. [PubMed] [Cross Ref]
197. Douglas J.G., Munro J.F., Kitchin A.H., Muir A.L., Proudfoot A.T. Pulmonary hypertension and fenfluramine. Br. Med. J. Clin. Res. Ed. 1981;283:881–883. doi: 10.1136/bmj.283.6296.881. [PMC free article] [PubMed] [Cross Ref]
198. Sitbon O., Humbert M., Simonneau G. Pulmonary Circulation: Diseases and Their Treatment. 3rd ed. CRC Press; Boca Raton, FL, USA: 2011. Pulmonary hypertension related to appetite suppressants.
199. Chin K.M., Channick R.N., Rubin L.J. Is methamphetamine use associated with idiopathic pulmonary arterial hypertension? Chest. 2006;130:1657–1663. doi: 10.1378/chest.130.6.1657. [PubMed] [Cross Ref]
200. Schaiberger P.H., Kennedy T.C., Miller F.C., Gal J., Petty T.L. Pulmonary hypertension associated with long-term inhalation of “crank” methamphetamine. Chest. 1993;104:614–616. doi: 10.1378/chest.104.2.614. [PubMed] [Cross Ref]
201. Montani D., Seferian A., Savale L., Simonneau G., Humbert M. Drug-induced pulmonary arterial hypertension: A recent outbreak. Eur. Respir. Rev. 2013;22:244–250. doi: 10.1183/09059180.00003313. [PubMed] [Cross Ref]
202. Gonçalves C.L., Rezin G.T., Ferreira G.K., Jeremias I.C., Cardoso M.R., Valvassori S.S., Munhoz B.J.P., Borges G.D., Bristot B.N., Leffa D.D., et al. Effects of acute and chronic administration of fenproporex on DNA damage parameters in young and adult rats. Mol. Cell. Biochem. 2013;380:171–176. doi: 10.1007/s11010-013-1670-2. [PubMed] [Cross Ref]
203. Alvarenga T.A., Andersen M.L., Ribeiro D.A., Araujo P., Hirotsu C., Costa J.L., Battisti M.C., Tufik S. Single exposure to cocaine or ecstasy induces DNA damage in brain and other organs of mice. Addict. Biol. 2010;15:96–99. doi: 10.1111/j.1369-1600.2009.00179.x. [PubMed] [Cross Ref]
204. Andreazza A.C., Kauer-Sant’Anna M., Frey B.N., Stertz L., Zanotto C., Ribeiro L., Giasson K., Valvassori S.S., Réus G.Z., Salvador M., et al. Effects of mood stabilizers on DNA damage in an animal model of mania. J. Psychiatry Neurosci. 2008;33:516–524. [PMC free article] [PubMed]
205. Agarwal K., Mukherjee A., Sharma A., Sharma R., Bhardwaj K.R., Sen S. Clastogenic effect of fenfluramine in mice bone marrow cells in vivo. Environ. Mol. Mutagen. 1992;19:323–326. doi: 10.1002/em.2850190410. [PubMed] [Cross Ref]
206. Johnson Z., Venters J., Guarraci F.A., Zewail-Foote M. Methamphetamine induces DNA damage in specific regions of the female rat brain. Clin. Exp. Pharmacol. Physiol. 2015;42:570–575. doi: 10.1111/1440-1681.12404. [PubMed] [Cross Ref]
207. Nakagawa Y., Tayama S., Ogata A., Suzuki T., Ishii H. ATP-generating glycolytic substrates prevent N-nitrosofenfluramine-induced cytotoxicity in isolated rat hepatocytes. Chem. Biol. Interact. 2006;164:93–101. doi: 10.1016/j.cbi.2006.08.024. [PubMed] [Cross Ref]
208. Parolini M., Magni S., Castiglioni S., Binelli A. Amphetamine exposure imbalanced antioxidant activity in the bivalve Dreissena polymorpha causing oxidative and genetic damage. Chemosphere. 2016;144:207–213. doi: 10.1016/j.chemosphere.2015.08.025. [PubMed] [Cross Ref]
209. Da Silva C.J., dos Santos J.E., Satie Takahashi C. An evaluation of the genotoxic and cytotoxic effects of the anti-obesity drugs sibutramine and fenproporex. Hum. Exp. Toxicol. 2010;29:187–197. doi: 10.1177/0960327109358732. [PubMed] [Cross Ref]
210. Perfeito R., Cunha-Oliveira T., Rego A.C. Reprint of: Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease-resemblance to the effect of amphetamine drugs of abuse. Free Radic. Biol. Med. 2013;62:186–201. doi: 10.1016/j.freeradbiomed.2013.05.042. [PubMed] [Cross Ref]
211. Bengel D., Isaacs K.R., Heils A., Lesch K.P., Murphy D.L. The appetite suppressant d-fenfluramine induces apoptosis in human serotonergic cells. Neuroreport. 1998;9:2989–2993. doi: 10.1097/00001756-199809140-00013. [PubMed] [Cross Ref]
212. Eddahibi S., Adnot S. Anorexigen-induced pulmonary hypertension and the serotonin (5-HT) hypothesis: Lessons for the future in pathogenesis. Respir. Res. 2002;3:9. doi: 10.1186/rr181. [PMC free article] [PubMed] [Cross Ref]
213. Alwan S., Bandoli G., Chambers C.D. Maternal use of selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. Clin. Pharmacol. Ther. 2016 doi: 10.1002/cpt.376. [PubMed] [Cross Ref]
214. Fornaro E., Li D., Pan J., Belik J. Prenatal exposure to fluoxetine induces fetal pulmonary hypertension in the rat. Am. J. Respir. Crit. Care Med. 2007;176:1035–1040. doi: 10.1164/rccm.200701-163OC. [PubMed] [Cross Ref]
215. Sadoughi A., Roberts K.E., Preston I.R., Lai G.P., McCollister D.H., Farber H.W., Hill N.S. Use of selective serotonin reuptake inhibitors and outcomes in pulmonary arterial hypertension. Chest. 2013;144:531–541. doi: 10.1378/chest.12-2081. [PubMed] [Cross Ref]
216. Dhalla I.A., Juurlink D.N., Gomes T., Granton J.T., Zheng H., Mamdani M.M. Selective serotonin reuptake inhibitors and pulmonary arterial hypertension: A case-control study. Chest. 2012;141:348–353. doi: 10.1378/chest.11-0426. [PubMed] [Cross Ref]
217. Eddahibi S., Humbert M., Fadel E., Raffestin B., Darmon M., Capron F., Simonneau G., Dartevelle P., Hamon M., Adnot S. Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J. Clin. Investig. 2001;108:1141–1150. doi: 10.1172/JCI200112805. [PMC free article] [PubMed] [Cross Ref]
218. Eddahibi S., Hanoun N., Lanfumey L., Lesch K.P., Raffestin B., Hamon M., Adnot S. Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene. J. Clin. Investig. 2000;105:1555–1562. doi: 10.1172/JCI8678. [PMC free article] [PubMed] [Cross Ref]
219. Gürbüzel M., Oral E., Kizilet H., Halici Z., Gulec M. Genotoxic evaluation of selective serotonin-reuptake inhibitors by use of the somatic mutation and recombination test in Drosophila melanogaster. Mutat. Res. 2012;748:17–20. doi: 10.1016/j.mrgentox.2012.06.004. [PubMed] [Cross Ref]
220. Djordjevic J., Djordjevic A., Adzic M., Elaković I., Matić G., Radojcic M.B. Fluoxetine affects antioxidant system and promotes apoptotic signaling in Wistar rat liver. Eur. J. Pharmacol. 2011;659:61–66. doi: 10.1016/j.ejphar.2011.03.003. [PubMed] [Cross Ref]
221. Alzahrani H.A.S. Sister chromatid exchanges and sperm abnormalities produced by antidepressant drug fluoxetine in mouse treated in vivo. Eur. Rev. Med. Pharmacol. Sci. 2012;16:2154–2161. [PubMed]
222. Riggin L., Koren G. Effects of selective serotonin reuptake inhibitors on sperm and male fertility. Can. Fam. Physician. 2015;61:529–530.
223. Attia S.M., Bakheet S.A. Citalopram at the recommended human doses after long-term treatment is genotoxic for male germ cell. Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc. 2013;53:281–285. doi: 10.1016/j.fct.2012.11.051. [PubMed] [Cross Ref]
224. Tanrikut C., Feldman A.S., Altemus M., Paduch D.A., Schlegel P.N. Adverse effect of paroxetine on sperm. Fertil. Steril. 2010;94:1021–1026. doi: 10.1016/j.fertnstert.2009.04.039. [PubMed] [Cross Ref]
225. Fox B.D., Azoulay L., Dell’Aniello S., Langleben D., Lapi F., Benisty J., Suissa S. The use of antidepressants and the risk of idiopathic pulmonary arterial hypertension. Can. J. Cardiol. 2014;30:1633–1639. doi: 10.1016/j.cjca.2014.09.031. [PubMed] [Cross Ref]
226. Czarny P., Kwiatkowski D., Kacperska D., Kawczyńska D., Talarowska M., Orzechowska A., Bielecka-Kowalska A., Szemraj J., Gałecki P., Śliwiński T. Elevated level of DNA damage and impaired repair of oxidative DNA damage in patients with recurrent depressive disorder. Med. Sci. Monit. Int. Med. J. Exp. Clin. Res. 2015;21:412–418. [PMC free article] [PubMed]
227. Black C.N., Bot M., Scheffer P.G., Cuijpers P., Penninx B.W.J.H. Is depression associated with increased oxidative stress? A systematic review and meta-analysis. Psychoneuroendocrinology. 2015;51:164–175. doi: 10.1016/j.psyneuen.2014.09.025. [PubMed] [Cross Ref]
228. Lacave R., Larsen C.-J., Robert J. Cancérologie Fondamentale. John Libbey Eurotext; Paris, France: 2005.
229. Kondo N., Takahashi A., Ono K., Ohnishi T. DNA damage induced by alkylating agents and repair pathways. J. Nucleic Acids. 2010;2010:543531. doi: 10.4061/2010/543531. [PMC free article] [PubMed] [Cross Ref]
230. Fu D., Calvo J.A., Samson L.D. Balancing repair and tolerance of DNA damage caused by alkylating agents. Nat. Rev. Cancer. 2012;12:104–120. doi: 10.1038/nrc3185. [PMC free article] [PubMed] [Cross Ref]
231. Hoorn C.M., Wagner J.G., Petry T.W., Roth R.A. Toxicity of mitomycin C toward cultured pulmonary artery endothelium. Toxicol. Appl. Pharmacol. 1995;130:87–94. doi: 10.1006/taap.1995.1012. [PubMed] [Cross Ref]
232. Lushnikova E.L., Molodykh O.P., Nepomnyashchikh L.M., Bakulina A.A., Sorokina Y.A. Ultrastructurural picture of cyclophosphamide-induced damage to the liver. Bull. Exp. Biol. Med. 2011;151:751–756. doi: 10.1007/s10517-011-1432-7. [PubMed] [Cross Ref]
233. Ranchoux B., Günther S., Quarck R., Chaumais M.-C., Dorfmüller P., Antigny F., Dumas S.J., Raymond N., Lau E., Savale L., et al. Chemotherapy-induced pulmonary hypertension: Role of alkylating agents. Am. J. Pathol. 2015;185:356–371. doi: 10.1016/j.ajpath.2014.10.021. [PubMed] [Cross Ref]
234. Perros F., Günther S., Ranchoux B., Godinas L., Antigny F., Chaumais M.-C., Dorfmüller P., Hautefort A., Raymond N., Savale L., et al. Mitomycin-induced pulmonary veno-occlusive disease: Evidence from human disease and animal models. Circulation. 2015;132:834–847. doi: 10.1161/CIRCULATIONAHA.115.014207. [PubMed] [Cross Ref]
235. Montani D., Lau E.M., Dorfmüller P., Girerd B., Jaïs X., Savale L., Perros F., Nossent E., Garcia G., Parent F., et al. Pulmonary veno-occlusive disease. Eur. Respir. J. 2016;47:1518–1534. doi: 10.1183/13993003.00026-2016. [PubMed] [Cross Ref]
236. Siegel D., Franklin W.A., Ross D. Immunohistochemical detection of NAD(P)H:quinone oxidoreductase in human lung and lung tumors. Clin. Cancer Res. 1998;4:2065–2070. [PubMed]
237. Cooper J.A., Merrill W.W., Reynolds H.Y. Cyclophosphamide modulation of bronchoalveolar cellular populations and macrophage oxidative metabolism. Possible mechanisms of pulmonary pharmacotoxicity. Am. Rev. Respir. Dis. 1986;134:108–114. [PubMed]
238. Hamano Y., Sugimoto H., Soubasakos M.A., Kieran M., Olsen B.R., Lawler J., Sudhakar A., Kalluri R. Thrombospondin-1 associated with tumor microenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression. Cancer Res. 2004;64:1570–1574. doi: 10.1158/0008-5472.CAN-03-3126. [PubMed] [Cross Ref]
239. Ohtani T., Nakamura T., Toda K.-I., Furukawa F. Cyclophosphamide enhances TNF-α-induced apoptotic cell death in murine vascular endothelial cell. FEBS Lett. 2006;580:1597–1600. doi: 10.1016/j.febslet.2006.01.092. [PubMed] [Cross Ref]
240. Mytilineou C., Kramer B.C., Yabut J.A. Glutathione depletion and oxidative stress. Parkinsonism Relat. Disord. 2002;8:385–387. doi: 10.1016/S1353-8020(02)00018-4. [PubMed] [Cross Ref]
241. Srivastava A., Poonkuzhali B., Shaji R.V., George B., Mathews V., Chandy M., Krishnamoorthy R. Glutathione S-transferase M1 polymorphism: A risk factor for hepatic venoocclusive disease in bone marrow transplantation. Blood. 2004;104:1574–1577. doi: 10.1182/blood-2003-11-3778. [PubMed] [Cross Ref]
242. DeLeve L.D. Cellular target of cyclophosphamide toxicity in the murine liver: Role of glutathione and site of metabolic activation. Hepatology. 1996;24:830–837. doi: 10.1002/hep.510240414. [PubMed] [Cross Ref]
243. Montani D., Lau E.M., Descatha A., Jaïs X., Savale L., Andujar P., Bensefa-Colas L., Girerd B., Zendah I., Le Pavec J., et al. Occupational exposure to organic solvents: A risk factor for pulmonary veno-occlusive disease. Eur. Respir. J. 2015;46:1721–1731. doi: 10.1183/13993003.00814-2015. [PubMed] [Cross Ref]
244. Hu C., Jiang L., Geng C., Zhang X., Cao J., Zhong L. Possible involvement of oxidative stress in trichloroethylene-induced genotoxicity in human HepG2 cells. Mutat. Res. 2008;652:88–94. doi: 10.1016/j.mrgentox.2008.01.002. [PubMed] [Cross Ref]
245. Roth R.A., Reindel J.F. Lung vascular injury from monocrotaline pyrrole, a putative hepatic metabolite. Adv. Exp. Med. Biol. 1991;283:477–487. [PubMed]
246. Yan C.C., Huxtable R.J. Release of an alkylating metabolite, dehydromonocrotaline, from the isolated liver perfused with the pyrrolizidine alkaloid, monocrotaline. Proc. West. Pharmacol. Soc. 1994;37:107–108. [PubMed]
247. Mattocks A.R., Jukes R. Trapping and measurement of short-lived alkylating agents in a recirculating flow system. Chem. Biol. Interact. 1990;76:19–30. doi: 10.1016/0009-2797(90)90031-H. [PubMed] [Cross Ref]
248. Meloche J., Pflieger A., Vaillancourt M., Paulin R., Potus F., Zervopoulos S., Graydon C., Courboulin A., Breuils-Bonnet S., Tremblay E., et al. Role for DNA damage signaling in pulmonary arterial hypertension. Circulation. 2014;129:786–797. doi: 10.1161/CIRCULATIONAHA.113.006167. [PubMed] [Cross Ref]
249. Meloche J., Le Guen M., Potus F., Vinck J., Ranchoux B., Johnson I., Antigny F., Tremblay E., Breuils-Bonnet S., Perros F., et al. miR-223 reverses experimental pulmonary arterial hypertension. Am. J. Physiol. Cell Physiol. 2015;309:C363–C372. doi: 10.1152/ajpcell.00149.2015. [PubMed] [Cross Ref]
250. Zhong Z., Wen Z., Darnell J.E. Stat3: A STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 1994;264:95–98. doi: 10.1126/science.8140422. [PubMed] [Cross Ref]
251. Meloche J., Potus F., Vaillancourt M., Bourgeois A., Johnson I., Deschamps L., Chabot S., Ruffenach G., Henry S., Breuils-Bonnet S., et al. Bromodomain-containing protein 4: The epigenetic origin of pulmonary arterial hypertension. Circ. Res. 2015;117:525–535. doi: 10.1161/CIRCRESAHA.115.307004. [PubMed] [Cross Ref]
252. Wang M., Wu W., Wu W., Rosidi B., Zhang L., Wang H., Iliakis G. PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways. Nucleic Acids Res. 2006;34:6170–6182. doi: 10.1093/nar/gkl840. [PMC free article] [PubMed] [Cross Ref]
253. Byrne M., Wray J., Reinert B., Wu Y., Nickoloff J., Lee S.-H., Hromas R., Williamson E. Mechanisms of oncogenic chromosomal translocations. Ann. N. Y. Acad. Sci. 2014;1310:89–97. doi: 10.1111/nyas.12370. [PubMed] [Cross Ref]
254. Wray J., Williamson E.A., Singh S.B., Wu Y., Cogle C.R., Weinstock D.M., Zhang Y., Lee S.-H., Zhou D., Shao L., et al. PARP1 is required for chromosomal translocations. Blood. 2013;121:4359–4365. doi: 10.1182/blood-2012-10-460527. [PubMed] [Cross Ref]
255. Soni A., Siemann M., Grabos M., Murmann T., Pantelias G.E., Iliakis G. Requirement for Parp-1 and DNA ligases 1 or 3 but not of Xrcc1 in chromosomal translocation formation by backup end joining. Nucleic Acids Res. 2014;42:6380–6392. doi: 10.1093/nar/gku298. [PMC free article] [PubMed] [Cross Ref]
256. Kumar R. Nuclear Signaling Pathways and Targeting Transcription in Cancer. Springer Science & Business Media; New York, NY, USA: 2013.
257. Hu S., Qu Y., Xu X., Xu Q., Geng J., Xu J. Nuclear survivin and its relationship to DNA damage repair genes in non-small cell lung cancer investigated using tissue array. PLoS ONE. 2013;8:990 doi: 10.1371/annotation/03b700e2-348b-4b1c-b068-4760c32de19e. [PMC free article] [PubMed] [Cross Ref]
258. Paulin R., Meloche J., Jacob M.H., Bisserier M., Courboulin A., Bonnet S. Dehydroepiandrosterone inhibits the Src/STAT3 constitutive activation in pulmonary arterial hypertension. Am. J. Physiol. Heart Circ. Physiol. 2011;301:H1798–H1809. doi: 10.1152/ajpheart.00654.2011. [PubMed] [Cross Ref]
259. McMurtry M.S., Archer S.L., Altieri D.C., Bonnet S., Haromy A., Harry G., Bonnet S., Puttagunta L., Michelakis E.D. Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J. Clin. Investig. 2005;115:1479–1491. doi: 10.1172/JCI23203. [PMC free article] [PubMed] [Cross Ref]
260. Li M., Vattulainen S., Aho J., Orcholski M., Rojas V., Yuan K., Helenius M., Taimen P., Myllykangas S., de Jesus Perez V., et al. Loss of bone morphogenetic protein receptor 2 is associated with abnormal DNA repair in pulmonary arterial hypertension. Am. J. Respir. Cell Mol. Biol. 2014;50:1118–1128. doi: 10.1165/rcmb.2013-0349OC. [PubMed] [Cross Ref]
261. De Jesus Perez V.A., Yuan K., Lyuksyutova M.A., Dewey F., Orcholski M.E., Shuffle E.M., Mathur M., Yancy L., Rojas V., Li C.G., et al. Whole-exome sequencing reveals topbp1 as a novel gene in idiopathic pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 2014;189:1260–1272. doi: 10.1164/rccm.201310-1749OC. [PMC free article] [PubMed] [Cross Ref]
262. Lee Y., Katyal S., Downing S.M., Zhao J., Russell H.R., McKinnon P.J. Neurogenesis requires TopBP1 to prevent catastrophic replicative DNA damage in early progenitors. Nat. Neurosci. 2012;15:819–826. doi: 10.1038/nn.3097. [PMC free article] [PubMed] [Cross Ref]
263. Yamane K., Wu X., Chen J. A DNA damage-regulated BRCT-containing protein, TopBP1, is required for cell survival. Mol. Cell. Biol. 2002;22:555–566. doi: 10.1128/MCB.22.2.555-566.2002. [PMC free article] [PubMed] [Cross Ref]
264. Mäkiniemi M., Hillukkala T., Tuusa J., Reini K., Vaara M., Huang D., Pospiech H., Majuri I., Westerling T., Mäkelä T.P., et al. BRCT domain-containing protein TopBP1 functions in DNA replication and damage response. J. Biol. Chem. 2001;276:30399–30406. doi: 10.1074/jbc.M102245200. [PubMed] [Cross Ref]
265. Ngo J., Matsuyama M., Kim C., Poventud-Fuentes I., Bates A., Siedlak S.L., Lee H., Doughman Y.Q., Watanabe M., Liner A., et al. Bax deficiency extends the survival of Ku70 knockout mice that develop lung and heart diseases. Cell Death Dis. 2015;6:e1706. doi: 10.1038/cddis.2015.11. [PMC free article] [PubMed] [Cross Ref]
266. Jacquin S., Rincheval V., Mignotte B., Richard S., Humbert M., Mercier O., Londoño-Vallejo A., Fadel E., Eddahibi S. Inactivation of p53 is sufficient to induce development of pulmonary hypertension in rats. PLoS ONE. 2015;10:990 doi: 10.1371/journal.pone.0131940. [PMC free article] [PubMed] [Cross Ref]
267. Mizuno S., Bogaard H.J., Kraskauskas D., Alhussaini A., Gomez-Arroyo J., Voelkel N.F., Ishizaki T. p53 Gene deficiency promotes hypoxia-induced pulmonary hypertension and vascular remodeling in mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 2011;300:L753–L761. doi: 10.1152/ajplung.00286.2010. [PubMed] [Cross Ref]
268. Mouraret N., Marcos E., Abid S., Gary-Bobo G., Saker M., Houssaini A., Dubois-Rande J.-L., Boyer L., Boczkowski J., Derumeaux G., et al. Activation of lung p53 by Nutlin-3a prevents and reverses experimental pulmonary hypertension. Circulation. 2013;127:1664–1676. doi: 10.1161/CIRCULATIONAHA.113.002434. [PMC free article] [PubMed] [Cross Ref]
269. Potus F., LeGuen M., Provencher S., Meloche J., Bonnet S. DNA damage at the dawn of micro-RNA pathway impairment in pulmonary arterial hypertension. RNA Dis. 2015;2 doi: 10.14800/rd.810. [Cross Ref]
270. Courboulin A., Ranchoux B., Cohen-Kaminsky S., Perros F., Bonnet S. MicroRNA networks in pulmonary arterial hypertension: Share mechanisms with cancer? Curr. Opin. Oncol. 2016;28:72–82. doi: 10.1097/CCO.0000000000000253. [PubMed] [Cross Ref]
271. Fang E.F., Scheibye-Knudsen M., Chua K.F., Mattson M.P., Croteau D.L., Bohr V.A. Nuclear DNA damage signalling to mitochondria in ageing. Nat. Rev. Mol. Cell Biol. 2016 doi: 10.1038/nrm.2016.14. [PMC free article] [PubMed] [Cross Ref]
272. King A., Selak M.A., Gottlieb E. Succinate dehydrogenase and fumarate hydratase: Linking mitochondrial dysfunction and cancer. Oncogene. 2006;25:4675–4682. doi: 10.1038/sj.onc.1209594. [PubMed] [Cross Ref]
273. Boland M.L., Chourasia A.H., Macleod K.F. Mitochondrial dysfunction in cancer. Front. Oncol. 2013;3:292. doi: 10.3389/fonc.2013.00292. [PMC free article] [PubMed] [Cross Ref]
274. Sureshbabu A., Bhandari V. Targeting mitochondrial dysfunction in lung diseases: Emphasis on mitophagy. Front. Physiol. 2013;4 doi: 10.3389/fphys.2013.00384. [PMC free article] [PubMed] [Cross Ref]
275. Tang X., Luo Y.-X., Chen H.-Z., Liu D.-P. Mitochondria, endothelial cell function, and vascular diseases. Front. Physiol. 2014;5 doi: 10.3389/fphys.2014.00175. [PMC free article] [PubMed] [Cross Ref]
276. Xu W., Koeck T., Lara A.R., Neumann D., DiFilippo F.P., Koo M., Janocha A.J., Masri F.A., Arroliga A.C., Jennings C., et al. Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proc. Natl. Acad. Sci. USA. 2007;104:1342–1347. doi: 10.1073/pnas.0605080104. [PubMed] [Cross Ref]
277. Dromparis P., Michelakis E.D. Mitochondria in vascular health and disease. Annu. Rev. Physiol. 2013;75:95–126. doi: 10.1146/annurev-physiol-030212-183804. [PubMed] [Cross Ref]
278. Dromparis P., Sutendra G., Michelakis E.D. The role of mitochondria in pulmonary vascular remodeling. J. Mol. Med. 2010;88:1003–1010. doi: 10.1007/s00109-010-0670-x. [PubMed] [Cross Ref]
279. Quintero M., Colombo S.L., Godfrey A., Moncada S. Mitochondria as signaling organelles in the vascular endothelium. Proc. Natl. Acad. Sci. USA. 2006;103:5379–5384. doi: 10.1073/pnas.0601026103. [PubMed] [Cross Ref]
280. Kluge M.A., Fetterman J.L., Vita J.A. Mitochondria and Endothelial Function. Circ. Res. 2013;112:1171–1188. doi: 10.1161/CIRCRESAHA.111.300233. [PMC free article] [PubMed] [Cross Ref]
281. Vaseva A.V., Moll U.M. The mitochondrial p53 pathway. Biochim. Biophys. Acta Bioenerg. 2009;1787:414–420. doi: 10.1016/j.bbabio.2008.10.005. [PMC free article] [PubMed] [Cross Ref]
282. Bonnet S., Michelakis E.D., Porter C.J., Andrade-Navarro M.A., Thébaud B., Bonnet S., Haromy A., Harry G., Moudgil R., McMurtry M.S., et al. An abnormal mitochondrial–hypoxia inducible factor-1α–Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats similarities to human pulmonary arterial hypertension. Circulation. 2006;113:2630–2641. doi: 10.1161/CIRCULATIONAHA.105.609008. [PubMed] [Cross Ref]
283. Paulin R., Michelakis E.D. The metabolic theory of pulmonary arterial hypertension. Circ. Res. 2014;115:148–164. doi: 10.1161/CIRCRESAHA.115.301130. [PubMed] [Cross Ref]
284. Sutendra G., Dromparis P., Wright P., Bonnet S., Haromy A., Hao Z., McMurtry M.S., Michalak M., Vance J.E., Sessa W.C., et al. The role of Nogo and the mitochondria-endoplasmic reticulum unit in pulmonary hypertension. Sci. Transl. Med. 2011;3:88ra55. doi: 10.1126/scitranslmed.3002194. [PMC free article] [PubMed] [Cross Ref]
285. Dromparis P., Paulin R., Stenson T.H., Haromy A., Sutendra G., Michelakis E.D. Attenuating endoplasmic reticulum stress as a novel therapeutic strategy in pulmonary hypertension. Circulation. 2013;127:115–125. doi: 10.1161/CIRCULATIONAHA.112.133413. [PubMed] [Cross Ref]
286. Cottrill K.A., Chan S.Y. Metabolic dysfunction in pulmonary hypertension: The expanding relevance of the Warburg effect. Eur. J. Clin. Investig. 2013;43:855–865. doi: 10.1111/eci.12104. [PMC free article] [PubMed] [Cross Ref]
287. Antigny F., Hautefort A., Meloche J., Belacel-Ouari M., Manoury B., Rucker-Martin C., Péchoux C., Potus F., Nadeau V., Tremblay E., et al. Potassium-channel subfamily k-member 3 (KCNK3) contributes to the development of pulmonary arterial hypertension. Circulation. 2016 doi: 10.1161/CIRCULATIONAHA.115.020951. [PubMed] [Cross Ref]
288. Boucherat O., Chabot S., Antigny F., Perros F., Provencher S., Bonnet S. Potassium channels in pulmonary arterial hypertension. Eur. Respir. J. 2015;46:1167–1177. doi: 10.1183/13993003.00798-2015. [PubMed] [Cross Ref]
289. McMurtry M.S., Bonnet S., Wu X., Dyck J.R.B., Haromy A., Hashimoto K., Michelakis E.D. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ. Res. 2004;95:830–840. doi: 10.1161/01.RES.0000145360.16770.9f. [PubMed] [Cross Ref]
290. Michelakis E.D., McMurtry M.S., Wu X.-C., Dyck J.R.B., Moudgil R., Hopkins T.A., Lopaschuk G.D., Puttagunta L., Waite R., Archer S.L. Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: Role of increased expression and activity of voltage-gated potassium channels. Circulation. 2002;105:244–250. doi: 10.1161/hc0202.101974. [PubMed] [Cross Ref]
291. Diebold I., Hennigs J.K., Miyagawa K., Li C.G., Nickel N.P., Kaschwich M., Cao A., Wang L., Reddy S., Chen P.-I., et al. BMPR2 preserves mitochondrial function and DNA during reoxygenation to promote endothelial cell survival and reverse pulmonary hypertension. Cell Metab. 2015;21:596–608. doi: 10.1016/j.cmet.2015.03.010. [PMC free article] [PubMed] [Cross Ref]
292. Fessel J.P., Flynn C.R., Robinson L.J., Penner N.L., Gladson S., Kang C.J., Wasserman D.H., Hemnes A.R., West J.D. Hyperoxia synergizes with mutant bone morphogenic protein receptor 2 to cause metabolic stress, oxidant injury, and pulmonary hypertension. Am. J. Respir. Cell Mol. Biol. 2013;49:778–787. doi: 10.1165/rcmb.2012-0463OC. [PMC free article] [PubMed] [Cross Ref]
293. Gomez-Arroyo J., Mizuno S., Szczepanek K., van Tassell B., Natarajan R., dos Remedios C.G., Drake J.I., Farkas L., Kraskauskas D., Wijesinghe D.S., et al. Metabolic gene remodeling and mitochondrial dysfunction in failing right ventricular hypertrophy due to pulmonary arterial hypertension. Circ. Heart Fail. 2013;6:136–144. doi: 10.1161/CIRCHEARTFAILURE.111.966127. [PMC free article] [PubMed] [Cross Ref]
294. Sutendra G., Dromparis P., Paulin R., Zervopoulos S., Haromy A., Nagendran J., Michelakis E.D. A metabolic remodeling in right ventricular hypertrophy is associated with decreased angiogenesis and a transition from a compensated to a decompensated state in pulmonary hypertension. J. Mol. Med. 2013;91:1315–1327. doi: 10.1007/s00109-013-1059-4. [PubMed] [Cross Ref]
295. Archer S.L., Fang Y.-H., Ryan J.J., Piao L. Metabolism and bioenergetics in the right ventricle and pulmonary vasculature in pulmonary hypertension. Pulm. Circ. 2013;3:144–152. doi: 10.4103/2045-8932.109960. [PMC free article] [PubMed] [Cross Ref]
296. Cline S.D. Mitochondrial DNA damage and its consequences for mitochondrial gene expression. Biochim. Biophys. Acta. 2012;1819:979–991. doi: 10.1016/j.bbagrm.2012.06.002. [PMC free article] [PubMed] [Cross Ref]
297. Barja G., Herrero A. Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals. FASEB J. 2000;14:312–318. [PubMed]
298. Yakes F.M., Van Houten B. Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc. Natl. Acad. Sci. USA. 1997;94:514–519. doi: 10.1073/pnas.94.2.514. [PubMed] [Cross Ref]
299. Tadi S.K., Sebastian R., Dahal S., Babu R.K., Choudhary B., Raghavan S.C. Microhomology-mediated end joining is the principal mediator of double-strand break repair during mitochondrial DNA lesions. Mol. Biol. Cell. 2016;27:223–235. doi: 10.1091/mbc.E15-05-0260. [PMC free article] [PubMed] [Cross Ref]
300. Grishko V., Solomon M., Wilson G.L., LeDoux S.P., Gillespie M.N. Oxygen radical-induced mitochondrial DNA damage and repair in pulmonary vascular endothelial cell phenotypes. Am. J. Physiol. 2001;280:L1300–L1308. [PubMed]
301. López-López L., Nieves-Plaza M., del Castro M.R., Font Y.M., Torres-Ramos C.A., Vilá L.M., Ayala-Peña S. Mitochondrial DNA damage is associated with damage accrual and disease duration in patients with systemic lupus erythematosus. Lupus. 2014;23:1133–1141. doi: 10.1177/0961203314537697. [PMC free article] [PubMed] [Cross Ref]
302. Akdogan A., Kilic L., Dogan I., Okutucu S., Er E., Kaya B., Coplu L., Calguneri M., Tokgozoglu L., Ertenli I. Pulmonary hypertension in systemic lupus erythematosus: Pulmonary thromboembolism is the leading cause. J. Clin. Rheumatol. Pract. Rep. Rheum. Musculoskelet. Dis. 2013;19:421–425. doi: 10.1097/RHU.0000000000000037. [PubMed] [Cross Ref]
303. Asherson R.A. Pulmonary hypertension in systemic lupus erythematosus. J. Rheumatol. 1990;17:414–415. doi: 10.1136/bmj.287.6398.1024-a. [PubMed] [Cross Ref]
304. Fetterman J.L., Holbrook M., Westbrook D.G., Brown J.A., Feeley K.P., Bretón-Romero R., Linder E.A., Berk B.D., Weisbrod R.M., Widlansky M.E., et al. Mitochondrial DNA damage and vascular function in patients with diabetes mellitus and atherosclerotic cardiovascular disease. Cardiovasc. Diabetol. 2016;15:53. doi: 10.1186/s12933-016-0372-y. [PMC free article] [PubMed] [Cross Ref]
305. Cheng Y., Ren X., Gowda A.S.P., Shan Y., Zhang L., Yuan Y.-S., Patel R., Wu H., Huber-Keener K., Yang J.W., et al. Interaction of Sirt3 with OGG1 contributes to repair of mitochondrial DNA and protects from apoptotic cell death under oxidative stress. Cell Death Dis. 2013;4:e731. doi: 10.1038/cddis.2013.254. [PMC free article] [PubMed] [Cross Ref]
306. Paulin R., Dromparis P., Sutendra G., Gurtu V., Zervopoulos S., Bowers L., Haromy A., Webster L., Provencher S., Bonnet S., et al. Sirtuin 3 deficiency is associated with inhibited mitochondrial function and pulmonary arterial hypertension in rodents and humans. Cell Metab. 2014;20:827–839. doi: 10.1016/j.cmet.2014.08.011. [PubMed] [Cross Ref]
307. Szczesny B., Brunyanszki A., Olah G., Mitra S., Szabo C. Opposing roles of mitochondrial and nuclear PARP1 in the regulation of mitochondrial and nuclear DNA integrity: Implications for the regulation of mitochondrial function. Nucleic Acids Res. 2014;42:13161–13173. doi: 10.1093/nar/gku1089. [PMC free article] [PubMed] [Cross Ref]
308. Fang E.F., Scheibye-Knudsen M., Brace L.E., Kassahun H., SenGupta T., Nilsen H., Mitchell J.R., Croteau D.L., Bohr V.A. Defective mitophagy in XPA via PARP1 hyperactivation and NAD/+SIRT1 Reduction. Cell. 2014;157:882–896. doi: 10.1016/j.cell.2014.03.026. [PMC free article] [PubMed] [Cross Ref]

Articles from International Journal of Molecular Sciences are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)