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1.  Interplay Between Heme Oxygenase-1 and miR-378 Affects Non-Small Cell Lung Carcinoma Growth, Vascularization, and Metastasis 
Antioxidants & Redox Signaling  2013;19(7):644-660.
Aims: Heme oxygenase-1 (HO-1, HMOX1) can prevent tumor initiation; while in various tumors, it has been demonstrated to promote growth, angiogenesis, and metastasis. Here, we investigated whether HMOX1 can modulate microRNAs (miRNAs) and regulate human non-small cell lung carcinoma (NSCLC) development. Results: Stable HMOX1 overexpression in NSCLC NCI-H292 cells up-regulated tumor-suppressive miRNAs, whereas it significantly diminished the expression of oncomirs and angiomirs. The most potently down-regulated was miR-378. HMOX1 also up-regulated p53, down-regulated angiopoietin-1 (Ang-1) and mucin-5AC (MUC5AC), reduced proliferation, migration, and diminished angiogenic potential. Carbon monoxide was a mediator of HMOX1 effects on proliferation, migration, and miR-378 expression. In contrast, stable miR-378 overexpression decreased HMOX1 and p53; while enhanced expression of MUC5AC, vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and Ang-1, and consequently increased proliferation, migration, and stimulation of endothelial cells. Adenoviral delivery of HMOX1 reversed miR-378 effect on the proliferation and migration of cancer cells. In vivo, HMOX1 overexpressing tumors were smaller, less vascularized and oxygenated, and less metastatic. Overexpression of miR-378 exerted opposite effects. Accordingly, in patients with NSCLC, HMOX1 expression was lower in metastases to lymph nodes than in primary tumors. Innovation and Conclusion: In vitro and in vivo data indicate that the interplay between HMOX1 and miR-378 significantly modulates NSCLC progression and angiogenesis, suggesting miR-378 as a new therapeutic target. Rebound Track: This work was rejected during standard peer review and rescued by Rebound Peer Review (Antioxid Redox Signal 16, 293–296, 2012) with the following serving as open reviewers: James F. George, Mahin D. Maines, Justin C. Mason, and Yasufumi Sato. Antioxid. Redox Signal. 19, 644–660.
PMCID: PMC3740397  PMID: 23617628
2.  Heme Oxygenase-1 Is Required for Angiogenic Function of Bone Marrow-Derived Progenitor Cells: Role in Therapeutic Revascularization 
Antioxidants & Redox Signaling  2014;20(11):1677-1692.
Aims: Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that can be down-regulated in diabetes. Its importance for mature endothelium has been described, but its role in proangiogenic progenitors is not well known. We investigated the effect of HO-1 on the angiogenic potential of bone marrow-derived cells (BMDCs) and on blood flow recovery in ischemic muscle of diabetic mice. Results: Lack of HO-1 decreased the number of endothelial progenitor cells (Lin−CD45−cKit-Sca-1+VEGFR-2+) in murine bone marrow, and inhibited the angiogenic potential of cultured BMDCs, affecting their survival under oxidative stress, proliferation, migration, formation of capillaries, and paracrine proangiogenic potential. Transcriptome analysis of HO-1−/− BMDCs revealed the attenuated up-regulation of proangiogenic genes in response to hypoxia. Heterozygous HO-1+/− diabetic mice subjected to hind limb ischemia exhibited reduced local expression of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), stromal cell-derived factor 1 (SDF-1), VEGFR-1, VEGFR-2, and CXCR-4. This was accompanied by impaired revascularization of ischemic muscle, despite a strong mobilization of bone marrow-derived proangiogenic progenitors (Sca-1+CXCR-4+) into peripheral blood. Blood flow recovery could be rescued by local injections of conditioned media harvested from BMDCs, but not by an injection of cultured BMDCs. Innovation: This is the first report showing that HO-1 haploinsufficiency impairs tissue revascularization in diabetes and that proangiogenic in situ response, not progenitor cell mobilization, is important for blood flow recovery. Conclusions: HO-1 is necessary for a proper proangiogenic function of BMDCs. A low level of HO-1 in hyperglycemic mice decreases restoration of perfusion in ischemic muscle, which can be rescued by a local injection of conditioned media from cultured BMDCs. Antioxid. Redox Signal. 20, 1677–1692.
PMCID: PMC3961799  PMID: 24206054
3.  Heme Oxygenase-1 Inhibits Myoblast Differentiation by Targeting Myomirs 
Antioxidants & Redox Signaling  2012;16(2):113-127.
Heme oxygenase-1 (HMOX1) is a cytoprotective enzyme degrading heme to biliverdin, iron ions, and carbon monoxide, whose expression is induced in response to oxidative stress. Its overexpression has been suggested as a strategy improving survival of transplanted muscle precursors. Results: Here we demonstrated that HMOX1 inhibits differentiation of myoblasts and modulates miRNA processing: downregulates Lin28 and DGCR8, lowers the total pool of cellular miRNAs, and specifically blocks induction of myomirs. Genetic or pharmacological activation of HMOX1 in C2C12 cells reduces the abundance of miR-1, miR-133a, miR-133b, and miR-206, which is accompanied by augmented production of SDF-1 and miR-146a, decreased expression of MyoD, myogenin, and myosin, and disturbed formation of myotubes. Similar relationships between HMOX1 and myomirs were demonstrated in murine primary satellite cells isolated from skeletal muscles of HMOX1+/+, HMOX1+/−, and HMOX1−/− mice or in human rhabdomyosarcoma cell lines. Inhibition of myogenic development is independent of antioxidative properties of HMOX1. Instead it is mediated by CO-dependent inhibition of c/EBPδ binding to myoD promoter, can be imitated by SDF-1, and partially reversed by enforced expression of miR-133b and miR-206. Control C2C12 myoblasts injected to gastrocnemius muscles of NOD-SCID mice contribute to formation of muscle fibers. In contrast, HMOX1 overexpressing C2C12 myoblasts form fast growing, hyperplastic tumors, infiltrating the surrounding tissues, and disseminating to the lungs. Innovation: We evidenced for the first time that HMOX1 inhibits differentiation of myoblasts, affects the miRNA processing enzymes, and modulates the miRNA transcriptome. Conclusion: HMOX1 improves the survival of myoblasts, but concurrently through regulation of myomirs, may act similarly to oncogenes, increasing the risk of hyperplastic growth of myogenic precursors. Antioxid. Redox Signal. 16, 113–127.
PMCID: PMC3222100  PMID: 21827279
4.  Heme Oxygenase-1 Regulates the Progression of K/BxN Serum Transfer Arthritis 
PLoS ONE  2012;7(12):e52435.
Heme oxygenase-1 (HO-1) is induced in many cell types as a defense mechanism against stress. We have investigated the possible role of endogenous HO-1 in the effector phase of arthritis using the K/BxN serum transfer model of arthritis in HO-1 heterozygous and homozygous knock-out mice.
Methodology/Principal Findings
Arthritis was induced in C57/Black-6 xFVB (HO-1+/+, HO-1+/− and HO-1−/−) mice by intraperitoneal injection of 150 µl serum from arthritic K/BxN mice at days 0 and 2. Blood was collected and animals were sacrificed at day 10. Histological analysis was performed in ankle sections. The levels of inflammatory mediators were measured in serum and paw homogenates by enzyme-linked immunosorbent assay or Multiplex technology. The incidence of arthritis was higher in HO-1+/− and HO-1−/− groups compared with HO-1+/+. The inflammatory response was aggravated in HO-1+/− mice as shown by arthritic score and the migration of inflammatory cells that could be related to the enhancement of CXCL-1 production. In addition, the HO-1+/− group showed proteoglycan depletion significantly higher than HO-1+/+ mice. Serum levels of matrix metalloproteinase-3, monocyte chemotactic protein-1, plasminogen activator inhibitor-1, E-selectin and intercellular adhesion molecule-1 were increased in arthritic HO-1−/− mice, whereas vascular endothelial growth factor and some cytokines such as interferon-γ showed a reduction compared to HO-1+/+ or HO-1+/− mice. In addition, down-regulated gene expression of ferritin, glutathione S-reductase A1 and superoxide dismutase-2 was observed in the livers of arthritic HO-1+/− animals.
Endogenous HO-1 regulates the production of systemic and local inflammatory mediators and plays a protective role in K/BxN serum transfer arthritis.
PMCID: PMC3527514  PMID: 23285041
5.  Targeting Nrf2-Mediated Gene Transcription by Triterpenoids and Their Derivatives 
Biomolecules & Therapeutics  2012;20(6):499-505.
Chemoprevention represents a strategy designed to protect cells or tissues against various carcinogens and carcinogenic metabolites derived from exogenous or endogenous sources. Recent studies indicate that plant-derived triterpenoids, like oleanolic acid, may exert cytoprotective functions via regulation of the activity of different transcription factors. The chemopreventive effects may be mediated through induction of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor. Activation of Nrf2 by triterpenoids induces the expression of phase 2 detoxifying and antioxidant enzymes such as NAD(P)H quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1) - proteins which can protect cells or tissues against various toxic metabolites. On the other hand, inhibition of other transcription factors, like NF-κB leads to the decrease in the pro-inflammatory gene expression. Moreover, the modulation of microRNAs activity may constitute a new mechanism responsible for valuable effects of triterpenoids. Recently, based on the structure of naturally occurring triterpenoids and with involvement of bioinformatics and computational chemistry, many synthetic analogs with improved biological properties have been obtained. Data from in vitro and in vivo experiments strongly suggest synthetic derivatives as promising candidates in the chemopreventive and chemotherapeutic strategies.
PMCID: PMC3762293  PMID: 24009841
Anti-oxidant response; Betulin; Chemoprevention; Oleanolic acid; Triterpenoids
6.  Opposite effects of HIF-1α and HIF-2α on the regulation of IL-8 expression in endothelial cells 
Free Radical Biology & Medicine  2011;51(10):1882-1892.
Recently we have shown that hypoxia as well as overexpression of the stable form of hypoxia-inducible factor-1α (HIF-1α) diminished the expression of interleukin-8 (IL-8) by inhibition of the Nrf2 transcription factor in HMEC-1 cells. Because HIF isoforms may exert different effects, we aimed to examine the influence of HIF-2α on IL-8 expression in endothelial cells. In contrast to HIF-1α, overexpression of HIF-2α obtained by adenoviral transduction resulted in increased expression of IL-8 in an Nrf2-independent way. Importantly, HIF-2α augmented the activity of SP-1, a transcription factor involved in IL-8 regulation and known coactivator of c-Myc. Additionally, HIF-1 decreased, whereas HIF-2 increased, c-Myc expression, and silencing of Mxi-1, a c-Myc antagonist, restored IL-8 expression downregulated by HIF-1α or hypoxia. Accordingly, binding of c-Myc to the IL-8 promoter was abolished in hypoxia. Importantly, both severe (0.5% O2) and mild (5% O2) hypoxia diminished IL-8 expression despite the stabilization of both HIF-1 and HIF-2. This study reveals the opposite roles of HIF-1α and HIF-2α in the regulation of IL-8 expression in endothelial cells. However, despite stabilization of both isoforms in hypoxia the effect of HIF-1 is predominant, and downregulation of IL-8 expression in hypoxia is caused by attenuation of Nrf2 and c-Myc.
Graphical abstract
► HIF-1 decreases whereas HIF-2 increases the expression of IL-8 in endothelial cells. ► SP-1 and c-Myc are involved in the HIF-2α-dependent IL-8 upregulation. ► Mxi-1, a c-Myc antagonist, mediates IL-8 diminishment by hypoxia/HIF-1α. ► Inhibition of Nrf2 activity by hypoxia/HIF-1α adds to the downregulation of IL-8. ► Both HIF isoforms are stabilized in hypoxia but the effect of HIF-1α is predominant.
PMCID: PMC3202637  PMID: 21925595
AdHIF-1α/AdHIF-2α, adenoviral vectors containing HIF-1α or HIF-2α cDNA, respectively; ARE, antioxidant-response element; ARNT, aryl hydrocarbon receptor nuclear translocator; GFP, green fluorescent protein; HIF, hypoxia-inducible factor; HO-1, heme oxygenase-1; IL-8, interleukin-8; NQO1, NAD(P)H:quinone oxidoreductase; SEAP, secreted alkaline phosphatase; siRNA, small interfering RNA; TP, thymidine phosphorylase; VEGF, vascular endothelial growth factor; Angiogenesis; SP-1; c-Myc; Transcription factor; Free radicals
7.  Aristolochic acid I and ochratoxin A differentially regulate VEGF expression in porcine kidney epithelial cells—The involvement of SP-1 and HIFs transcription factors 
Toxicology Letters  2011;204(2-3):118-126.
► AAI increases whereas OTA decreases production of proangiogenic VEGF. ► The upregulation of VEGF expression by AAI is caused by induction of SP-1 and HIFs. ► Hypoxia prevents OTA-diminished VEGF production ► The effect of hypoxia on OTA-reduced VEGF is mediated by HIF-2α but not HIF-1α.
Aristolochic acid I (AAI) and ochratoxin A (OTA) cause chronic kidney diseases. Recently, the contribution of hypoxic injuries and angiogenic disturbances to nephropathies has been suggested, but underlying mechanisms have not been fully clarified yet.
In porcine kidney epithelial cell line, LLC-PK1 cells, treatment with non-toxic doses of AAI increased whereas with OTA decreased production of vascular endothelial growth factor (VEGF), the angiogenic factor with well-defined functions in kidney. Moreover, the activity of transcription factors regulating VEGF expression was differentially affected by examined compounds. Activity of hypoxia inducible factors (HIFs) and SP-1 was increased by AAI but diminished by OTA. Interestingly, AP-1 activity was inhibited while NFκB was not influenced by both toxins. Mithramycin A, a SP-1 inhibitor, as well as chetomin, an inhibitor of HIFs, reversed AAI-induced up-regulation of VEGF synthesis, indicating the importance of SP-1 and HIFs in this effect. Additionally, adenoviral overexpression of HIF-2α but not HIF-1α prevented OTA-diminished VEGF production suggesting the protective effect of this isoform towards the consequences exerted by OTA.
These observations provide new insight into complex impact of AAI and OTA on angiogenic gene regulation. Additionally, it adds to our understanding of hypoxia influence on nephropathies pathology.
PMCID: PMC3154282  PMID: 21554934
AA, aristolochic acid; AAI, aristolochic acid I; AAII, aristolochic acid II; AA-ATN, aristolochic acid-induced acute tubular necrosis; AAN, aristolochic acid-induced nephropathy; AdGFP, adenoviral vectors containing GFP cDNA; AdHIF-1,-2α, adenoviral vectors containing HIF-1,-2α cDNA; β-gal, β-galactosidase; BEN, Balkan endemic nephropathy; CKDs, chronic kidney diseases; EMT, epithelial to mesenchymal cell transformation; GFP, green fluorescent protein; HIF, hypoxia inducible factor; HRE, hypoxia responsive element; HRP, horseradish peroxidase; LDH, lactate dehydrogenase; LLC-PK1, porcine kidney epithelial cell line; IARC, The International Agency for Research on Cancer; OTA, ochratoxin A; ROS, reactive oxygen species; RT, room temperature; TGFβ, transforming growth factor β; VEGF, vascular endothelial growth factor; Nephropathy; Kidney diseases; Vascular endothelial growth factor; Angiogenesis; Hypoxia; LLC-PK1
8.  Effects of apoE genotype on macrophage inflammation and heme oxygenase-1 expression 
In order to gain a more comprehensive understanding of the aetiology of apolipoprotein E4 genotype-cardiovascular disease (CVD) associations, the impact of the apoE genotype on the macrophage inflammatory response was examined. The murine monocyte–macrophage cell line (RAW 264.7) stably transfected to produce equal amounts of human apoE3 or apoE4 was used. Following LPS stimulation, apoE4-macrophages showed higher and lower concentrations of tumour necrosis factor alpha (pro-inflammatory) and interleukin 10 (anti-inflammatory), respectively, both at mRNA and protein levels. In addition, increased expression of heme oxygenase-1 (a stress-induced anti-inflammatory protein) was observed in the apoE4-cells. Furthermore, in apoE4-macrophages, an enhanced transactivation of the key redox sensitive transcription factor NF-κB was shown. Current data indicate that apoE4 macrophages have an altered inflammatory response, which may contribute to the higher CVD risk observed in apoE4 carriers.
PMCID: PMC2096715  PMID: 17416347
apoE genotype; Macrophage; Cytokines; Nuclear factor κB; Heme oxygenase-1; Tumour necrosis factor α; Inflammation; Oxidative stress; Redox signalling
10.  Effects of apoE genotype on macrophage inflammation and heme oxygenase-1 expression 
In order to gain a more comprehensive understanding of the aetiology of apolipoprotein E4 genotype-cardiovascular disease (CVD) associations, the impact of the apoE genotype on the macrophage inflammatory response was examined. The murine monocyte–macrophage cell line (RAW 264.7) stably transfected to produce equal amounts of human apoE3 or apoE4 was used. Following LPS stimulation, apoE4-macrophages showed higher and lower concentrations of tumour necrosis factor alpha (pro-inflammatory) and interleukin 10 (anti-inflammatory), respectively, both at mRNA and protein levels. In addition, increased expression of heme oxygenase-1 (a stress-induced anti-inflammatory protein) was observed in the apoE4-cells. Furthermore, in apoE4-macrophages, an enhanced transactivation of the key redox sensitive transcription factor NF-κB was shown. Current data indicate that apoE4 macrophages have an altered inflammatory response, which may contribute to the higher CVD risk observed in apoE4 carriers.
PMCID: PMC2096715  PMID: 17416347
apoE genotype; Macrophage; Cytokines; Nuclear factor κB; Heme oxygenase-1; Tumour necrosis factor α; Inflammation; Oxidative stress; Redox signalling
11.  Angiogenic transcriptome of human microvascular endothelial cells: Effect of hypoxia, modulation by atorvastatin 
Vascular pharmacology  2006;44(4):206-214.
Hypoxia changes expression of angiogenic genes. Statins were also reported to affect blood vessel formation. However, data on the effects of statins on endothelial cells in hypoxia are limited. Here, effect of hypoxia and atorvastatin was assessed in human microvascular endothelial cells (HMEC-1). Hypoxia (1% O2) up-regulated vascular endothelial growth factor-A (VEGF-A) but, unexpectedly, it decreased interleukin-8 (IL-8) and placenta growth factor (PlGF) expression. Atorvastatin (0.1–1 μM) attenuated PlGF in HMEC-1 in normoxia while it decreased VEGF-A and IL-8 production both in normoxia and hypoxia. Notably, the expression of VEGF-D, macrophage scavenger receptor-1 (MSR1), transforming growth factor β receptor III (TGFβR3) and inhibitor of DNA binding 3 (ID3) was augmented by atorvastatin in cells cultured in normoxia, while in hypoxia the statin attenuated their expression. These data showed that hypoxia influenced in the opposite way the expression of major endothelial genes, augmenting VEGF-A and decreasing IL-8 and PlGF. The influence of atorvastatin on angiogenic gene expression is complex, and final pro- or anti-angiogenic outcome of statin therapy remains to be established for numerous angiogenesis-related diseases.
PMCID: PMC1626524  PMID: 16481221
Statins; VEGF-A; IL-8; HIF-1; PlGF
12.  Atorvastatin prevents hypoxia-induced inhibition of endothelial nitric oxide synthase expression but does not affect heme oxygenase-1 in human microvascular endothelial cells 
Atherosclerosis  2006;187(1):26-30.
Beneficial cardiovascular effects of statins, the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are particularly assigned to the modulation of inflammation. Endothelial nitric oxide synthase (eNOS) and heme oxygenase-1 (HO-1) are listed among the crucial protective, anti-inflammatory genes in the vasculature. Here we show that atorvastatin at pharmacologically relevant concentration (0.1 μM) enhanced the expression of eNOS in human microvascular endothelial cells (HMEC-1). Moreover, atorvastatin prevented hypoxia-induced decrease in eNOS expression. However, in the same cells atorvastatin was ineffective in modulation of HO-1 protein level. Therefore, we suggest that the protective effect of statins at their pharmacological concentrations is not mediated by enhancement of HO-1 activity, but may involve eNOS.
PMCID: PMC1482780  PMID: 16620829
Angiogenesis; Atherosclerosis; Statins; Hypercholesterolemia
13.  Effect of heme and heme oxygenase-1 on vascular endothelial growth factor synthesis and angiogenic potency of human keratinocytes 
Free radical biology & medicine  2005;40(7):1250-1263.
Background: Skin injury leads to the release of heme, a potent prooxidant which is degraded by heme oxygenase-1 (HO-1) to carbon monoxide, iron, and biliverdin, subsequently reduced to bilirubin. Recently the involvement of HO-1 in angiogenesis has been shown; however, the role of heme and HO-1 in wound healing angiogenesis has not been yet investigated.
Results: Treatment of HaCaT keratinocytes with hemin (heme chloride) induced HO-1 expression and activity. The effect of heme on vascular endothelial growth factor (VEGF) synthesis is variable: induction is significant after a short, 6-h treatment with heme, while longer stimulation may attenuate its production. The involvement of HO-1 in VEGF synthesis was confirmed by inhibition of VEGF expression by SnPPIX, a blocker of HO activity and by attenuation of HO-1 mRNA expression with specific siRNA. Importantly, induction of HO-1 by hemin was able to overcome the inhibitory effect of high glucose on VEGF synthesis. Moreover, HO-1 expression was also induced in keratinocytes cultured in hypoxia, with concomitant augmentation of VEGF production, which was further potentiated by hemin stimulation. Accordingly, conditioned media from keratinocytes overexpressing HO-1 enhanced endothelial cell proliferation and augmented formation of capillaries in angiogenic assay in vitro.
Conclusions: HO-1 is involved in hemin-induced VEGF expression in HaCaT and may play a role in hypoxic regulation of this protein. HO-1 overexpression may be beneficial in restoring the proper synthesis of VEGF disturbed in diabetic conditions.
PMCID: PMC1414644  PMID: 16545694
HO-1; Reactive oxygen species; VEGF; HaCaT keratinocytes; Angiogenesis; Inflammation; Free radicals
14.  Atorvastatin Affects Several Angiogenic Mediators in Human Endothelial Cells 
The pleiotropic effects of statins, inhibitors of 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase, have been recently extended to the modulation of angiogenesis. Here, to get more insight into the statins action, the authors have investigated the effect of atorvastatin on the expression of several angiogenic and inflammatory genes in human umbilical endothelial cells (HUVECs). Atorvastatin was proangiogenic at the dose of 10 nM, and antiangiogenic at the concentrations of 1 to 10 μM. Moreover, these higher concentrations inhibited also the proliferation of HUVECs induced by vascular endothelial growth factor (VEGF). Lower doses of atorvastatin did not influence endothelial cell proliferation. Importantly, atorvastatin at the micromolar concentrations diminished the production of interleukin (IL)-8, a proinflammatory and proangiogenic chemokine, and inhibited the synthesis of urokinase plasminogen activator (uPA), a potent proinflammatory mediator. However, it decreased also the expression of plasminogen activator inhibitor-1 (PAI-1) and thrombospondin-1 (TSP-1), the inhibitors of angiogenesis. Atorvastatin stimulated the expression of angiopoietin (Ang)-2 and moderately enhanced the expression of endothelial nitric oxide synthase (eNOS), whereas heme oxygenase-1 (HO-1) was not significantly affected. In conclusion, the present findings points to other angiogenesis-related effects of atorvastatin, which may be of relevance to the beneficial influence of statins in cardiovascular system.
PMCID: PMC1398052  PMID: 16410222
Atherosclerosis; Cancer; Heme Oxygenase-1; Interleukin 8; Vascular Endothelial Growth Factor
15.  New Strategies for Cardiovascular Gene Therapy 
Cardiovascular diseases are among the major targets for gene therapy. Initially, clinical experiments of gene transfer of vascular endothelial growth factor (VEGF) improved vascularization and prevented the amputation in patients with critical leg ischemia. However, the majority of trials did not provide conclusive results and therefore further preclinical studies are required. Importantly, data indicate the necessity of regulated expression of angiogenic factors, particularly VEGF, to obtain the therapeutic effect. It is also suggested that the combined delivery of two or more genes may improve the formation of mature vasculature and therefore may be more effective in the amelioration of ischemia. Moreover, experimental approaches in animal models displayed the promise of gene transfer modulating the inflammatory processes and oxidant status of the cells. Particularly, the concept of preemptive gene therapy has been tested, and recent studies have demonstrated that overexpression of heme oxygenase-1 or extracellular superoxide dismutase can prevent heart injury by myocardial infarction induced several weeks after gene instillation. The combination of a preemptive strategy with regulated gene expression, using the vectors in which the therapeutic transgene is driven by exogenously or endogenously controllable promoter, offers another modality. However, we hypothesize that regulatable gene therapy, dependent on the activity of endogenous factors, might be prone to limitations owing to the potential disturbance in the expression of endogenous genes. Here, we demonstrated some indications of these drawbacks. Therefore, the final acceptance of these promising strategies for clinical trials requires careful validation in animal experiments.
PMCID: PMC1391923  PMID: 16456232
Gene therapy; angiogenesis; vascular endothelial growth factor; heme oxygenase; hypoxia inducible factor-1; nitric-oxide synthase; superoxide dismutase

Results 1-15 (15)