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1.  Heme Oxygenase-1, a Critical Arbitrator of Cell Death Pathways in Lung Injury and Disease 
Increases in cell death by programmed (ie., apoptosis, autophagy) or non-programmed mechanisms (ie., necrosis) occur during tissue injury, and may contribute to the etiology of several pulmonary or vascular disease states. The low molecular weight stress protein heme oxygenase-1 (HO-1) confers cytoprotection against cell death in various models of lung and vascular injury by inhibiting apoptosis, inflammation, and cell proliferation. HO-1 serves a vital metabolic function as the rate-limiting step in the heme degradation pathway and in the maintenance of iron homeostasis. The transcriptional induction of HO-1 occurs in response to multiple forms of chemical and physical cellular stress. The cytoprotective functions of HO-1 may be attributed to heme turnover, as well as to beneficial properties of its enzymatic reaction products: biliverdin-IXα, iron, and carbon monoxide (CO). Recent studies have demonstrated that HO-1 or CO inhibits stress-induced extrinsic and intrinsic apoptotic pathways in vitro. A variety of signaling molecules have been implicated in the cytoprotection conferred by HO-1/CO, including autophagic proteins, p38 mitogen activated protein kinase, signal transducer and activator of transcription proteins, nuclear factor-κB, phosphatydylinositol-3-kinase/Akt, and others. Enhanced HO-1 expression or the pharmacological application of HO end-products affords protection in preclinical models of tissue injury, including experimental and transplant-associated ischemia/reperfusion injury, promising potential future therapeutic applications.
doi:10.1016/j.freeradbiomed.2009.04.007
PMCID: PMC3078523  PMID: 19362144
2.  Heme Oxygenase-1: Its Therapeutic Roles in Inflammatory Diseases 
Heme oxygenase (HO)-1 is an inducible enzyme that catalyzes the first and rate-limiting step in the oxidative degradation of free heme into ferrous iron, carbon monoxide (CO), and biliverdin (BV), the latter being subsequently converted into bilirubin (BR). HO-1, once expressed during inflammation, forms high concentrations of its enzymatic by-products that can influence various biological events, and this expression is proven to be associated with the resolution of inflammation. The degradation of heme by HO-1 itself, the signaling actions of CO, the antioxidant properties of BV/BR, and the sequestration of ferrous iron by ferritin all concertedly contribute to the anti-inflammatory effects of HO-1. This review focuses on the anti-inflammatory mechanisms of HO-1 actions and its roles in inflammatory diseases.
doi:10.4110/in.2009.9.1.12
PMCID: PMC2803295  PMID: 20107533
heme oxygenase-1; carbon monoxide; bilirubin/biliverdin; inflammation; nuclear factor E2-related factor-2; mitogen-activated protein kinase
3.  Heme Oxygenase-1/Carbon Monoxide 
Heme oxygenase-1 (HO-1), a ubiquitous inducible stress-response protein, serves a major metabolic function in heme turnover. HO activity cleaves heme to form biliverdin-IXα, carbon monoxide (CO), and iron. Genetic experiments have revealed a central role for HO-1 in tissue homeostasis, protection against oxidative stress, and in the pathogenesis of disease. Four decades of research have witnessed not only progress in elucidating the molecular mechanisms underlying the regulation and function of this illustrious enzyme, but also have opened remarkable translational applications for HO-1 and its reaction products. CO, once regarded as a metabolic waste, can act as an endogenous mediator of cellular signaling and vascular function. Exogenous application of CO by inhalation or pharmacologic delivery can confer cytoprotection in preclinical models of lung/vascular injury and disease, based on anti-apoptotic, anti-inflammatory, and anti-proliferative properties. The bile pigments, biliverdin and bilirubin, end products of heme degradation, have also shown potential as therapeutics in vascular disease based on anti-inflammatory and anti-proliferative activities. Further translational and clinical trials research will unveil whether the HO-1 system or any of its reaction products can be successfully applied as molecular medicine in human disease.
doi:10.1165/rcmb.2009-0170TR
PMCID: PMC2742746  PMID: 19617398
carbon monoxide; bilirubin; heme oxygenase-1; lung injury
4.  BIGLUTAMINYL-BILIVERDIN IX ALPHA AS A HEME DEGRADATION PRODUCT IN THE DENGUE FEVER INSECT-VECTOR Aedes aegypti 
Biochemistry  2007;46(23):6822-6829.
Hemoglobin digestion in the midgut of hematophagous animals results in the release of its prosthetic group, heme, which is a pro-oxidant molecule. Heme enzymatic degradation is a protective mechanism that has been described in several organisms, including plants, bacteria, and mammals. This reaction is catalyzed by heme oxygenase and results in formation of carbon monoxide, ferrous ion, and biliverdin IXα. During digestion, a large amount of a green pigment is produced and secreted into the intestinal lumen of A. aegypti adult females. In the case of another blood-sucking insect, the kissing-bug Rhodnius prolixus, we have recently shown that heme degradation involves a complex pathway that generates dicysteinyl-biliverdin IX gamma. The light absorption spectrum of the Aedes purified pigment was similar to biliverdin, but its mobility on a reverse-phase chromatography column suggested a compound less hydrophobic than biliverdin IXα. Structural characterization by ESI-MS revealed that the mosquito pigment is the α isomer of biliverdin bound to two glutamine residues by an amide bond. This biglutaminyl-biliverdin is formed by oxidative cleavage of the heme porphyrin ring followed by two subsequent additions of glutamine residues to the biliverdin IXα. The role of this pathway in the adaptation of this insect vector to a blood-feeding habit is discussed.
doi:10.1021/bi700011d
PMCID: PMC2763637  PMID: 17508725
heme; heme oxygenase; biliverdin; detoxification; Aedes aegypti
5.  The IsdG-family of heme oxygenases degrades heme to a novel chromophore 
Molecular microbiology  2010;75(6):1529-1538.
Summary
Enzymatic heme catabolism by heme oxygenases is conserved from bacteria to humans and proceeds through a common mechanism leading to the formation of iron, carbon monoxide, and biliverdin. The first members of a novel class of heme oxygenases were recently identified in Staphylococcus aureus (IsdG and IsdI) and were termed the IsdG-family of heme oxygenases. Enzymes of the IsdG-family form tertiary structures distinct from those of the canonical heme oxygenase family, suggesting that IsdG-family members degrade heme via a unique reaction mechanism. Herein we report that the IsdG-family of heme oxygenases degrade heme to the oxo-bilirubin chromophore staphylobilin. We also present the crystal structure of heme-bound IsdI in which heme ruffling and constrained binding of oxygen is consistent with cleavage of the porphyrin ring at the β– or γ–meso carbons. Combined, these data establish that the IsdG-family of heme oxygenases degrade heme to a novel chromophore distinct from biliverdin.
doi:10.1111/j.1365-2958.2010.07076.x
PMCID: PMC3800195  PMID: 20180905
Staphylococcus aureus; heme oxygenase
6.  Cerebroprotective functions of HO-2 
Current pharmaceutical design  2008;14(5):443-453.
The constitutive isoform of heme oxygenase, HO-2, is highly expressed in the brain and in cerebral vessels. HO-2 functions in the brain have been evaluated using pharmacological inhibitors of the enzyme and HO-2 gene deletion in in vivo animal models and in cultured cells (neurons, astrocytes, cerebral vascular endothelial cells). Rapid activation of HO-2 via post-translational modifications without upregulation of HO-2 expression or HO-1 induction coincides with the increase in cerebral blood flow aimed at maintaining brain homeostasis and neuronal survival during seizures, hypoxia, and hypotension. Pharmacological inhibition or gene deletion of brain HO-2 exacerbates oxidative stress induced by seizures, glutamate, and inflammatory cytokines, and causes cerebral vascular injury. Carbon monoxide (CO) and bilirubin, the end products of HO-catalyzed heme degradation, have distinct cytoprotective functions. CO, by binding to a heme prosthetic group, regulates the key components of cell signaling, including BKCa channels, guanylyl cyclase, NADPH oxidase, and the mitochondria respiratory chain. Cerebral vasodilator effects of CO are mediated via activation of BKCa channels and guanylyl cyclase. CO, by inhibiting the major components of endogenous oxidantgenerating machinery, NADPH oxidase and the cytochrome C oxidase of the mitochondrial respiratory chain, blocks formation of reactive oxygen species. Bilirubin, via redox cycling with biliverdin, is a potent oxidant scavenger that removes preformed oxidants. Overall, HO-2 has dual housekeeping cerebroprotective functions by maintaining autoregulation of cerebral blood flow aimed at improving neuronal survival in a changing environment, and by providing an effective defense mechanism that blocks oxidant formation and prevents cell death caused by oxidative stress.
PMCID: PMC3587165  PMID: 18289071
Heme oxygenase; cerebral protection; cerebrovascular disease; oxidative stress; seizures; carbon monoxide; bilirubin
7.  Role of heme oxygenase-1 in microbial host defense 
Cellular microbiology  2008;11(2):199-207.
Summary
Heme oxygenase (HO)-1 is a cytoprotective enzyme that plays a critical role in defending the body against oxidant-induced injury during inflammatory processes. HO catalyzes the degradation of heme to carbon monoxide (CO), biliverdin, and ferrous iron. Biliverdin is converted to bilirubin, a potent endogenous antioxidant. CO has a number of biological functions, including anti-inflammatory properties. In various models of disease, HO-1 is known to play a critical role by ameliorating the pathological consequences of injury. In many of these models, the beneficial effects of HO-1 and its products of heme catabolism are by suppressing an inflammatory response. However, when investigating diseases due to microbial infections, inhibition of the inflammatory response could disrupt the ability of the immune system to eradicate an invading pathogen. Thus, questions remain regarding the role of HO-1 in microbial host defense. This microreview will address our present understanding of HO-1 and its functional significance in a variety of microbial infections.
doi:10.1111/j.1462-5822.2008.01261.x
PMCID: PMC3080039  PMID: 19016784
8.  Integrative Survival Response Evoked by Heme Oxygenase-1 and Heme Metabolites 
Heme oxygenase (HO) catalyzes the rate-limiting step in heme degradation to produce carbon monoxide (CO), iron, and biliverdin. Biliverdin is subsequently converted to bilirubin by its reductase, and iron is recycled for heme synthesis. The inducible HO isoform, HO-1, is involved in the protection of multiple tissues and organs. The mechanism of protective actions of HO-1 has not been completely elucidated, but recent evidence suggests that one or more of heme metabolites can mediate the protective effects of HO-1. Particularly, CO mimics the antioxidant, anti-inflammatory, anti-apoptotic and antiproliferative actions of HO-1. Many of these effects of CO depend on the production of cyclic guanosine monophosphate (cGMP), and the modulation of mitogen-activated protein kinase (MAPK) pathways. The transcription factors, including nuclear factor E2-related factor-2 (Nrf2), and their upstream kinases, including MAPK pathway, play an important regulatory role in HO-1 expression by dietary antioxidants and drugs. This review attempts to concisely summarize the molecular and biochemical characteristics of HO-1, with a discussion on the mechanisms of signal transduction and gene regulation that mediate the induction of HO-1 by dietary antioxidants and drugs. In addition, the cytoprotective roles of HO-1 shall be discussed from the perspective of each of the metabolic by-products.
doi:10.3164/jcbn.2008029
PMCID: PMC2386522  PMID: 18545641
heme oxygenase; antioxidant; anti-inflammation; anti-apoptosis; antiproliferation
9.  The Role of Heme Oxygenase-1 in Pulmonary Disease 
Heme oxygenase (HO)-1, the inducible isoform of heme oxygenase, is a cytoprotective enzyme that plays a central role in the defense against oxidative and inflammatory insults in the lung. HO-1 catalyzes the degradation of heme, a potent oxidant, into biliverdin, iron, and carbon monoxide (CO). These downstream products of heme catabolism have recently been found to mediate the antioxidant, antiapoptotic, antiproliferative, vasodilatory, and anti-inflammatory properties of HO-1. Although absence of HO-1 is rare in humans, a number of HO-1 promoter polymorphisms have been identified that may influence HO-1 expression in vivo and lead to disease states. This review will summarize studies that implicate HO-1 and heme metabolites in the pathophysiology of pulmonary disease and discuss recent advances in the therapeutic applications of HO-1.
doi:10.1165/rcmb.2006-0331TR
PMCID: PMC2176110  PMID: 16980551
HO-1; polymorphism; ARDS; pulmonary hypertension; COPD
10.  Cytoprotective role of heme oxygenase-1 and heme degradation derived end products in liver injury 
World Journal of Hepatology  2013;5(10):541-549.
The activation of heme oxygenase-1 (HO-1) appears to be an endogenous defensive mechanism used by cells to reduce inflammation and tissue damage in a number of injury models. HO-1, a stress-responsive enzyme that catabolizes heme into carbon monoxide (CO), biliverdin and iron, has previously been shown to protect grafts from ischemia/reperfusion and rejection. In addition, the products of the HO-catalyzed reaction, particularly CO and biliverdin/bilirubin, have been shown to exert protective effects in the liver against a number of stimuli, as in chronic hepatitis C and in transplanted liver grafts. Furthermore, the induction of HO-1 expression can protect the liver against damage caused by a number of chemical compounds. More specifically, the CO derived from HO-1-mediated heme catabolism has been shown to be involved in the regulation of inflammation; furthermore, administration of low concentrations of exogenous CO has a protective effect against inflammation. Both murine and human HO-1 deficiencies have systemic manifestations associated with iron metabolism, such as hepatic overload (with signs of a chronic hepatitis) and iron deficiency anemia (with paradoxical increased levels of ferritin). Hypoxia induces HO-1 expression in multiple rodent, bovine and monkey cell lines, but interestingly, hypoxia represses expression of the human HO-1 gene in a variety of human cell types (endothelial cells, epithelial cells, T cells). These data suggest that HO-1 and CO are promising novel therapeutic molecules for patients with inflammatory diseases. In this review, we present what is currently known regarding the role of HO-1 in liver injuries and in particular, we focus on the implications of targeted induction of HO-1 as a potential therapeutic strategy to protect the liver against chemically induced injury.
doi:10.4254/wjh.v5.i10.541
PMCID: PMC3812456  PMID: 24179613
Heme oxygenases; Bilirubin; Hepatitis C; Kupffer cells; Polymorphisms; Immunoregulatory; Hypoxia; Liver ischemia
11.  Scalable production of biliverdin IXα by Escherichia coli 
BMC Biotechnology  2012;12:89.
Background
Biliverdin IXα is produced when heme undergoes reductive ring cleavage at the α-methene bridge catalyzed by heme oxygenase. It is subsequently reduced by biliverdin reductase to bilirubin IXα which is a potent endogenous antioxidant. Biliverdin IXα, through interaction with biliverdin reductase, also initiates signaling pathways leading to anti-inflammatory responses and suppression of cellular pro-inflammatory events. The use of biliverdin IXα as a cytoprotective therapeutic has been suggested, but its clinical development and use is currently limited by insufficient quantity, uncertain purity, and derivation from mammalian materials. To address these limitations, methods to produce, recover and purify biliverdin IXα from bacterial cultures of Escherichia coli were investigated and developed.
Results
Recombinant E. coli strains BL21(HO1) and BL21(mHO1) expressing cyanobacterial heme oxygenase gene ho1 and a sequence modified version (mho1) optimized for E. coli expression, respectively, were constructed and shown to produce biliverdin IXα in batch and fed-batch bioreactor cultures. Strain BL21(mHO1) produced roughly twice the amount of biliverdin IXα than did strain BL21(HO1). Lactose either alone or in combination with glycerol supported consistent biliverdin IXα production by strain BL21(mHO1) (up to an average of 23. 5mg L-1 culture) in fed-batch mode and production by strain BL21 (HO1) in batch-mode was scalable to 100L bioreactor culture volumes. Synthesis of the modified ho1 gene protein product was determined, and identity of the enzyme reaction product as biliverdin IXα was confirmed by spectroscopic and chromatographic analyses and its ability to serve as a substrate for human biliverdin reductase A.
Conclusions
Methods for the scalable production, recovery, and purification of biliverdin IXα by E. coli were developed based on expression of a cyanobacterial ho1 gene. The purity of the produced biliverdin IXα and its ability to serve as substrate for human biliverdin reductase A suggest its potential as a clinically useful therapeutic.
doi:10.1186/1472-6750-12-89
PMCID: PMC3534565  PMID: 23176158
Biliverdin IXα; Heme oxygenase; Escherichia coli; HO1; Bilirubin; Anti-inflammatory; Biliverdin reductase; Bioreactor
12.  Heme Oxygenase in the Regulation of Vascular Biology: From Molecular Mechanisms to Therapeutic Opportunities 
Antioxidants & Redox Signaling  2011;14(1):137-167.
Abstract
Heme oxygenases (HOs) are the rate-limiting enzymes in the catabolism of heme into biliverdin, free iron, and carbon monoxide. Two genetically distinct isoforms of HO have been characterized: an inducible form, HO-1, and a constitutively expressed form, HO-2. HO-1 is a kind of stress protein, and thus regarded as a sensitive and reliable indicator of cellular oxidative stress. The HO system acts as potent antioxidants, protects endothelial cells from apoptosis, is involved in regulating vascular tone, attenuates inflammatory response in the vessel wall, and participates in angiogenesis and vasculogenesis. Endothelial integrity and activity are thought to occupy the central position in the pathogenesis of cardiovascular diseases. Cardiovascular disease risk conditions converge in the contribution to oxidative stress. The oxidative stress leads to endothelial and vascular smooth muscle cell dysfunction with increases in vessel tone, cell growth, and gene expression that create a pro-thrombotic/pro-inflammatory environment. Subsequent formation, progression, and obstruction of atherosclerotic plaque may result in myocardial infarction, stroke, and cardiovascular death. This background provides the rationale for exploring the potential therapeutic role for HO system in the amelioration of vascular inflammation and prevention of adverse cardiovascular outcomes. Antioxid. Redox Signal. 14, 137–167.
Introduction
HO Expression
Heme oxygenase-1
Mitogen-activated protein kinases
Nrf2 and Bach1
Activator protein-1
Biliverdin reductase
Heme oxygenase-2
HO By-Products
Carbon monoxide
Ferrous iron and ferritin
BV and BR
Effect of HO-1 on Vascular Inflammation
Cytokines, chemokines, and mediators
Macrophages
Endothelial cells
Control of Vascular Diseases by HO-1=CO
Ischemic diseases
Hypertension
Atherosclerosis
Diabetes mellitus
Therapeutic potential of HO-1=CO in vascular diseases
Effect of HO-1 on Angiogenesis
Cross-talk between the HO-1=CO and NOS=NO pathways
Effect of HO-1=CO pathway on vascular homeostasis
Regulation of VEGF expression by HO-1=CO
Restenosis and vasculopathy
Conclusion
doi:10.1089/ars.2010.3153
PMCID: PMC2988629  PMID: 20624029
13.  Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL. 
Journal of Clinical Investigation  1997;100(5):1209-1216.
Heme catabolic processes produce the antioxidants biliverdin and bilirubin, as well as the potent prooxidant free iron. Since these products have opposing effects on oxidative stress, it is not clear whether heme catabolism promotes or inhibits inflammatory processes, including atherosclerotic lesion formation. Heme oxygenase (HO) catalyzes the rate-limiting step of heme catabolism. We used cocultures of human aortic endothelial cells and smooth muscle cells to examine the possible role of HO in early atherosclerosis. Heme oxygenase-1 (HO-1), the inducible isoform of HO, was highly induced by mildly oxidized LDL, and augmented induction was observed with hemin pretreatment. This augmented HO-1 induction resulted in the reduction of monocyte chemotaxis in response to LDL oxidation. Conversely, inhibition of HO by a specific inhibitor, Sn-protoporphyrin IX, enhanced chemotaxis. Furthermore, pretreatment with biliverdin or bilirubin, the products of HO, reduced chemotaxis. Oxidized phospholipids in the mildly oxidized LDL appear to be responsible for HO-1 induction, since oxidized but not native arachidonic acid-containing phospholipids also induced HO-1. These results suggest that HO-1 induced by mildly oxidized LDL may protect against the induction of inflammatory responses in artery wall cells through the production of the antioxidants biliverdin and bilirubin.
PMCID: PMC508298  PMID: 9276739
14.  The Haptoglobin-CD163-Heme Oxygenase-1 Pathway for Hemoglobin Scavenging 
The haptoglobin- (Hp-) CD163-heme oxygenase-1 (HO-1) pathway is an efficient captor-receptor-enzyme system to circumvent the hemoglobin (Hb)/heme-induced toxicity during physiological and pathological hemolyses. In this pathway, Hb tightly binds to Hp leading to CD163-mediated uptake of the complex in macrophages followed by lysosomal Hp-Hb breakdown and HO-1-catalyzed conversion of heme into the metabolites carbon monoxide (CO), biliverdin, and iron. The plasma concentration of Hp is a limiting factor as evident during accelerated hemolysis, where the Hp depletion may cause serious Hb-induced toxicity and put pressure on backup protecting systems such as the hemopexin-CD91-HO pathway. The Hp-CD163-HO-1 pathway proteins are regulated by the acute phase mediator interleukin-6 (IL-6), but other regulatory factors indicate that this upregulation is a counteracting anti-inflammatory response during inflammation. The heme metabolites including bilirubin converted from biliverdin have overall an anti-inflammatory effect and thus reinforce the anti-inflammatory efficacy of the Hp-CD163-HO-1 pathway. Future studies of animal models of inflammation should further define the importance of the pathway in the anti-inflammatory response.
doi:10.1155/2013/523652
PMCID: PMC3678498  PMID: 23781295
15.  Leydig cell–derived heme oxygenase-1 regulates apoptosis of premeiotic germ cells in response to stress 
Stress-induced downregulation of spermatogenesis remains poorly understood. This study examined the induction of heme oxygenase-1 (HO-1), a carbon monoxide–generating inducible enzyme, in modulation of spermatogenesis. Rats were exposed to cadmium chloride (CdCl2), a stressor causing oligozoospermia, and HO-1–induction was monitored by following HO isozyme expression. CdCl2-treated testes increased HO-1 activity and suppressed microsomal cytochromes P450, which are required for steroidogenesis. CdCl2-elicited HO-1 occurred mostly in Leydig cells and coincided with CO generation, as judged by bilirubin-IXα immunoreactivity. Under these circumstances, germ cells in peripheral regions of seminiferous tubules exhibited apoptosis; laser flow cytometry revealed that these apoptotic cells involve diploid and tetraploid germ cells, suggesting involvement of spermatogonia and primary spermatocytes in CdCl2-elicited apoptosis. Pretreatment with zinc protoporphyrin-IX, an HO inhibitor, but not copper protoporphyrin-IX, which does not block the enzyme, attenuated the CdCl2-induced apoptosis. Such antiapoptotic effects of zinc protoporphyrin-IX were repressed by supplementation of dichloromethane, a CO donor. Upon CdCl2-treatment, both Sertoli cells and the germ cells upregulated Fas ligand; this event was also suppressed by zinc protoporphyrin-IX and restored by dichloromethane. Thus, Leydig cells appear to use HO-1–derived CO to trigger apoptosis of premeiotic germ cells and thereby modulate spermatogenesis under conditions of stress.
doi:10.1172/JCI13190
PMCID: PMC150871  PMID: 11854317
16.  Heme oxygenase-1: a novel therapeutic target for gastrointestinal diseases 
Heme oxygenase-1 (HO-1) is the rate-limiting enzyme in the catabolism of heme, followed by production of biliverdin, free iron and carbon monoxide (CO). HO-1 is a stress-responsive protein induced by various oxidative agents. Recent studies demonstrate that the expression of HO-1 in response to different inflammatory mediators may contribute to the resolution of inflammation and has protective effects in several organs against oxidative injury. Although the mechanism underlying the anti-inflammatory actions of HO-1 remains poorly defined, both CO and biliverdin/bilirubin have been implicated in this response. In the gastrointestinal tract, HO-1 is shown to be transcriptionally induced in response to oxidative stress, preconditioning and acute inflammation. Recent studies suggest that the induction of HO-1 expression plays a critical protective role in intestinal damage models induced by ischemia-reperfusion, indomethacin, lipopolysaccharide-associated sepsis, trinitrobenzene sulfonic acid, and dextran sulfate sodium, indicating that activation of HO-1 may act as an endogenous defensive mechanism to reduce inflammation and tissue injury in the gastrointestinal tract. In addition, CO derived from HO-1 is shown to be involved in the regulation in gastro-intestinal motility. These in vitro and in vivo data suggest that HO-1 may be a novel therapeutic target in patients with gastrointestinal diseases.
doi:10.3164/jcbn.10-61
PMCID: PMC3045685  PMID: 21373265
Bach1; bilirubin; carbon monoxide; heme oxygenase; indomethacin; Nrf2; ulcerative colitis
17.  Raised levels of exhaled carbon monoxide are associated with an increased expression of heme oxygenase-1 in airway macrophages in asthma: a new marker of oxidative stress 
Thorax  1998;53(8):668-672.
BACKGROUND—Chronic inflammatory diseases are associated with an increased production of oxidants. Induction of a stress protein, heme oxygenase (HO) HO-1, is a cytoprotective mechanism against oxidative cellular injury. HO-1 catabolises heme to bilirubin, free iron, and carbon monoxide (CO).
METHODS—Exhaled CO and sputum bilirubin levels were measured and HO-1 protein expression in airway macrophages was determined by Western blotting in asthmatic patients as levels of oxidants are raised in asthma and may induce HO-1.
RESULTS—Exhaled CO was significantly increased in 37 non-steroid treated asthmatic patients compared with 37 healthy subjects (5.8(95% CI 5.20 to 6.39) ppm vs 2.9 (2.51 to 3.28) ppm; p<0.0001) but was similar to normal in 25 patients who received corticosteroids (3.3 (95% CI 2.92 to 3.67) ppm; p>0.05). In non-treated asthmatic patients more HO-1 protein was expressed in airway macrophages than in normal subjects. Bilirubin levels in induced sputum were also higher than in normal subjects. Inhalation of hemin, a substrate for HO, significantly increased exhaled CO from 3.8 (95% CI 2.80to 4.87) ppm to 6.7 (95% CI 4.95 to 8.38 CI) ppm (p<0.05) with a concomitant decrease in exhaled nitric oxide levels, suggesting an interaction between the two systems.
CONCLUSIONS—Increased exhaled CO levels and HO-1 expression may reflect induction of HO-1 which may be inhibited by steroids. Measurement of exhaled CO, an index of HO activity in non-smoking subjects, may therefore be clinically useful in the detection and management of asthma and possibly other chronic inflammatory lung disorders.


PMCID: PMC1745300  PMID: 9828853
18.  Physiological significance of heme oxygenase in hypertension 
The last decade has witnessed an explosion in the elucidation of the role that the heme oxygenase system plays in human physiology. This system encompasses not only the heme degradative pathway, including heme oxygenase and biliverdin reductase, but also the products of heme degradation, carbon monoxide, iron, and biliverdin/bilirubin. Their role in diabetes, inflammation, heart disease, hypertension, transplantation, and pulmonary disease are areas of burgeoning research. The research has focused not only on heme itself but also on its metabolic products as well as endogenous compounds involved in a vast number of genetic and metabolic processes that are affected when heme metabolism is perturbed. It should be noted, however, that although the use of carbon monoxide and biliverdin/bilirubin as therapeutic agents has been successful, these agents can be toxic at high levels in tissue, e.g., kernicterus. Care must be used to ensure that when these compounds are used as therapeutic agents their deleterious effects are minimized or avoided. On balance, however, the strategies to target heme oxygenase-1 as described in this review offer promising therapeutic approaches to clinicians for the effective management of hypertension and renal function. The approaches detailed may prove to be seminal in the development of a new therapeutic strategy to treat hypertension.
doi:10.1016/j.biocel.2008.10.025
PMCID: PMC2745554  PMID: 19027871
Heme oxygenase; Hypertension; Carbon monoxide; Bilirubin; Adiponectin
19.  Increased levels of exhaled carbon monoxide in bronchiectasis: a new marker of oxidative stress 
Thorax  1998;53(10):867-870.
BACKGROUND—Bronchiectasis is a chronic inflammatory lung disease associated with increased production of oxidants due mostly to neutrophilic inflammation. Induction of heme oxygenase (HO-1) by reactive oxygen species is a general cytoprotective mechanism against oxidative stress. HO-1 catabolises heme to bilirubin, free iron and carbon monoxide (CO). Exhaled CO measurements may therefore reflect an oxidative stress and be clinically useful in the detection and management of inflammatory lung disorders.
METHODS—The levels of exhaled CO of 42 non-smoking patients with bronchiectasis treated or not treated with inhaled corticosteroids were compared with CO levels in 37 normal non-smoking subjects.
RESULTS—Levels of exhaled CO were raised in patients with bronchiectasis, both those treated with inhaled corticosteroids (n = 27,median 5.5 ppm, 95% CI 5.16 to 7.76) and those not treated with inhaled corticosteroids (n = 15, median 6.0 ppm, 95% CI 4.74 to 11.8), compared with normal subjects (n = 37, median 3.0 ppm, 95% CI 2.79 to 3.81, p = 0.0024). There was no correlation between exhaled CO and HbCO levels (r = 0.42, p = 0.12) in normal subjects (n = 7), nor between the urine cotinine concentration and exhaled CO levels (r = 0.2, p = 0.12).
CONCLUSIONS—Increased levels of exhaled CO may reflect induction of HO-1 and oxidative stress in bronchiectasis. Measurement of exhaled CO may be useful in the management of bronchiectasis and possibly other chronic inflammatory lung disorders.


PMCID: PMC1745084  PMID: 10193374
20.  Intestinal Absorption of Hemoglobin Iron-Heme Cleavage by Mucosal Heme Oxygenase 
Journal of Clinical Investigation  1974;54(6):1344-1352.
Hemoglobin and myoglobin are a major source of dietary iron in man. Heme, separated from these hemoproteins by intraluminal proteolysis, is absorbed intact by the intestinal mucosa. The absorbed heme is cleaved in the mucosal cell releasing inorganic iron. Although this mucosal heme-splitting activity initially was ascribed to xanthine oxidase, we investigated the possibility that it is catalyzed by microsomal heme oxygenase, an enzyme which converts heme to bilirubin, CO, and inorganic iron.
Microsomes prepared from rat intestinal mucosa contain enzymatic activity similar to that of heme oxygenase in liver and spleen. The intestinal enzyme requires NADPH; is completely inhibited by 50% CO; and produces bilirubin IX-α, identified spectrophotometrically and chromatographically. Moreover, duodenal heme oxygenase was shown to release inorganic 55Fe from 55Fe-heme. Along the intestinal tract, enzyme activity was found to be highest in the duodenum where hemoglobin iron absorption is reported to be most active. Furthermore, when rats were made iron deficient, duodenal heme oxygenase activity and hemoglobin-iron absorption rose to a comparable extent. Upon iron repletion of iron-deficient animals, duodenal enzyme activity returned towards control values. In contrast to heme oxygenase, duodenal xanthine oxidase activity fell sharply in iron deficiency and rose towards base line upon iron repletion.
Our findings suggest that mucosal heme oxygenase catalyzes the cleavage of heme absorbed in the intestinal mucosa and thus plays an important role in the absorption of hemoglobin iron. The mechanisms controlling this intestinal enzyme activity and the enzyme's role in the overall regulation of hemoglobin-iron absorption remain to be defined.
PMCID: PMC301689  PMID: 4436436
21.  Carbon Monoxide and Bilirubin 
Heme oxygenase (HO)-1, an inducible, low–molecular-weight stress protein, confers cellular and tissue protection in multiple models of injury and disease, including oxidative or inflammatory lung injury, ischemia/reperfusion (I/R) injuries, and vascular injury/disease. The tissue protection provided by HO-1 potentially relates to the endogenous production of the end products of its enzymatic activity: namely, biliverdin (BV)/bilirubin (BR), carbon monoxide (CO), and iron. Of these, CO and BV/BR show promise as possible therapeutic agents when applied exogenously in models of lung or vascular injury. CO activates intracellular signaling pathways that involve soluble guanylate cyclase and/or p38 mitogen-activated protein kinase. Although toxic at elevated concentrations, low concentrations of CO can confer antiinflammatory, antiapoptotic, antiproliferative, and vasodilatory effects. BV and BR are natural antioxidants that can provide protection against oxidative stress in cell culture and in plasma. Application of BV or BR protects against I/R injury in several organ models. Recent evidence has also demonstrated antiinflammatory and antiproliferative properties of these pigments. To date, evidence has accumulated for salutary effects of CO, BV, and/or BR in lung/vascular injury models, as well as in models of transplant-associated I/R injury. Thus, the exogenous application of HO end products may provide an alternative to pharmacologic or gene therapy approaches to harness the therapeutic potential of HO-1.
doi:10.1165/rcmb.2006-0333TR
PMCID: PMC2176112  PMID: 16980550
bilirubin; carbon monoxide; heme oxygenase-1; inflammation; ischemia/reperfusion
22.  Degradation of Heme in Gram-Negative Bacteria: the Product of the hemO Gene of Neisseriae Is a Heme Oxygenase 
Journal of Bacteriology  2000;182(23):6783-6790.
A full-length heme oxygenase gene from the gram-negative pathogen Neisseria meningitidis was cloned and expressed in Escherichia coli. Expression of the enzyme yielded soluble catalytically active protein and caused accumulation of biliverdin within the E. coli cells. The purified HemO forms a 1:1 complex with heme and has a heme protein spectrum similar to that previously reported for the purified heme oxygenase (HmuO) from the gram-positive pathogen Corynebacterium diphtheriae and for eukaryotic heme oxygenases. The overall sequence identity between HemO and these heme oxygenases is, however, low. In the presence of ascorbate or the human NADPH cytochrome P450 reductase system, the heme-HemO complex is converted to ferric-biliverdin IXα and carbon monoxide as the final products. Homologs of the hemO gene were identified and characterized in six commensal Neisseria isolates, Neisseria lactamica, Neisseria subflava, Neisseria flava, Neisseria polysacchareae, Neisseria kochii, and Neisseria cinerea. All HemO orthologs shared between 95 and 98% identity in amino acid sequences with functionally important residues being completely conserved. This is the first heme oxygenase identified in a gram-negative pathogen. The identification of HemO as a heme oxygenase provides further evidence that oxidative cleavage of the heme is the mechanism by which some bacteria acquire iron for further use.
PMCID: PMC111422  PMID: 11073924
23.  Heme Oxygenase-1 in Tumors 
Antioxidants & redox signaling  2007;9(12):2099-2117.
Heme oxygenase-1 (HO-1) catalyzes the oxidation of heme to biologically active products: carbon monoxide (CO), biliverdin, and ferrous iron. It participates in maintaining cellular homeostasis and plays an important protective role in the tissues by reducing oxidative injury, attenuating the inflammatory response, inhibiting cell apoptosis, and regulating cell proliferation. HO-1 is also an important proangiogenic mediator. Most studies have focused on the role of HO-1 in cardiovascular diseases, in which its significant, beneficial activity is well recognized. A growing body of evidence indicates, however, that HO-1 activation may play a role in carcinogenesis and can potently influence the growth and metastasis of tumors. HO-1 is very often upregulated in tumor tissues, and its expression is further increased in response to therapies. Although the exact effect can be tissue specific, HO-1 can be regarded as an enzyme facilitating tumor progression. Accordingly, inhibition of HO-1 can be suggested as a potential therapeutic approach sensitizing tumors to radiation, chemotherapy, or photodynamic therapy.
doi:10.1089/ars.2007.1659
PMCID: PMC2096718  PMID: 17822372
24.  Heme oxygenase-1 system and gastrointestinal inflammation: A short review 
Heme oxygenase-1 (HO-1) system catalyzes heme to biologically active products: carbon monoxide, biliverdin/bilirubin and free iron. It is involved in maintaining cellular homeostasis and many physiological and pathophysiological processes. A growing body of evidence indicates that HO-1 activation may play an important protective role in acute and chronic inflammation of gastrointestinal tract. This review focuses on the current understanding of the physiological significance of HO-1 induction and its possible roles in the gastrointestinal inflammation studied to date. The ability to upregulate HO-1 by pharmacological means or using gene therapy may offer therapeutic strategies for gastrointestinal inflammation in the future.
doi:10.3748/wjg.v17.i38.4283
PMCID: PMC3214703  PMID: 22090784
Heme oxygenase-1; Gastrointestinal inflammation
25.  Biliverdin Rescues the HO-2 Null Mouse Phenotype of Unresolved Chronic Inflammation Following Corneal Epithelial Injury 
The authors provide substantial evidence that the injured HO-2 null cornea, which experiences extensive oxidative stress, exaggerated inflammation, and impaired wound healing, can be rescued by the heme oxygenase product biliverdin, further supporting the notion that HO-2 is a critical cytoprotective system in the cornea.
Purpose.
The heme oxygenase system (HO-1 and HO-2) represents an intrinsic cytoprotective and anti-inflammatory pathway based on its ability to modulate leukocyte migration and to inhibit the expression of inflammatory cytokines and proteins by its products biliverdin/bilirubin and carbon monoxide. Corneal injury in HO-2 null mice leads to impaired healing and chronic inflammatory complications, including ulceration and neovascularization. The authors examined whether topically administered biliverdin can counteract the effects of HO deficiency in a corneal epithelial injury model.
Methods.
HO-2 null mice were treated with biliverdin 1 hour before epithelial injury and twice a day thereafter. Reepithelialization and neovascularization were assessed by fluorescein staining and vital microscopy, respectively, and were quantified by image analysis. Inflammation was quantified by histology and Gr-1–specific immunofluorescence, and oxidative stress was assessed by DHE fluorescence.
Results.
Treatment with biliverdin accelerated wound closure, inhibited neovascularization and reduced epithelial defects. It also reduced inflammation, as evidenced by a reduction in the appearance of inflammatory cells and the expression levels of inflammatory and oxidant proteins, including KC and NOXs.
Conclusions.
The results clearly show that biliverdin, directly or through its metabolism to bilirubin by biliverdin reductase—the expression of which is increased after injury—rescues the aberrant inflammatory phenotype, further underscoring the importance of the HO system in the cornea for the execution of an ordered inflammatory and reparative response.
doi:10.1167/iovs.10-6219
PMCID: PMC3109026  PMID: 21345995

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