Silencing the Adipocytokine NOV: A Novel Approach to Reversing Oxidative Stress-Induced Cardiometabolic Dysfunction.

OBJECTIVE: NOV/CCN3 is an adipocytokine recently linked to obesity, insulin resistance, and cardiometabolic dysfunction. NOV is manufactured and secreted from adipose tissue, with blood levels highly correlated with BMI. NOV levels are increased in obesity and a myriad of inflammatory diseases. Elevated NOV levels cause oxidative stress by increasing free radicals, decreasing antioxidants, and decreasing heme oxygenase (HO-1) levels, resulting in decreased vascular function. Silencing NOV in NOV knockout mice improved insulin sensitivity. We wanted to study how suppressing NOV expression in an obese animal model affected pathways and processes related to obesity, inflammation, and cardiometabolic function. This is the first study to investigate the interaction of adipose tissue-specific NOV/CCN3 and cardiometabolic function. METHODS: We constructed a lentivirus containing the adiponectin-promoter-driven shNOV to examine the effect of NOV inhibition (shNOV) in adipose tissue on the heart of mice fed a high-fat diet. Mice were randomly divided into three groups (five per group): (1) lean (normal diet), (2) high-fat diet (HFD)+ sham virus, and (3) HFD + shNOV lentivirus. Blood pressure, tissue inflammation, and oxygen consumption were measured. Metabolic and mitochondrial markers were studied in fat and heart tissues. RESULTS: Mice fed an HFD developed adipocyte hypertrophy, fibrosis, inflammation, and decreased mitochondrial respiration. Inhibiting NOV expression in the adipose tissue of obese mice by shNOV increased mitochondrial markers for biogenesis (PGC-1α, the nuclear co-activator of HO-1) and functional integrity (FIS1) and insulin signaling (AKT). The upregulation of metabolic and mitochondrial markers was also evident in the hearts of the shNOV mice with the activation of mitophagy. Using RNA arrays, we identified a subgroup of genes that highly correlated with increased adipocyte mitochondrial autophagy in shNOV-treated mice. A heat map analysis in obese mice confirmed that the suppression of NOV overrides the genetic susceptibility of adiposity and the associated detrimental metabolic changes and correlates with the restoration of anti-inflammatory, thermogenic, and mitochondrial genes. CONCLUSION: Our novel findings demonstrate that inhibiting NOV expression improves adipose tissue function in a positive way in cardiometabolic function by inducing mitophagy and improving mitochondrial function by the upregulation of PGC-1α, the insulin sensitivity signaling protein. Inhibiting NOV expression increases PGC-1, a key component of cardiac bioenergetics, as well as key signaling components of metabolic change, resulting in improved glucose tolerance, improved mitochondrial function, and decreased inflammation. These metabolic changes resulted in increased oxygen consumption, decreased adipocyte size, and improved cardiac metabolism and vascular function at the structural level. The crosstalk of the adipose tissue-specific deletion of NOV/CCN3 improved cardiovascular function, representing a novel therapeutic strategy for obesity-related cardiometabolic dysfunction.

Heme-oxygenase and lipid mediators in obesity and associated cardiometabolic diseases: Therapeutic implications.

Obesity-mediated metabolic syndrome remains the leading cause of death worldwide. Among many potential targets for pharmacological intervention, a promising strategy involves the heme oxygenase (HO) system, specifically its inducible form, HO-1. This review collects and updates much of the current knowledge relevant to pharmacology and clinical medicine concerning HO-1 in metabolic diseases and its effect on lipid metabolism. HO-1 has pleotropic effects that collectively reduce inflammation, while increasing vasodilation and insulin and leptin sensitivity. Recent reports indicate that HO-1 with its antioxidants via the effect of bilirubin increases formation of biologically active lipid metabolites such as epoxyeicosatrienoic acid (EET), omega-3 and other polyunsaturated fatty acids (PUFAs). Similarly, HO-1and bilirubin are potential therapeutic targets in the treatment of fat-induced liver diseases. HO-1-mediated upregulation of EET is capable not only of reversing endothelial dysfunction and hypertension, but also of reversing cardiac remodeling, a hallmark of the metabolic syndrome. This process involves browning of white fat tissue (i.e. formation of healthy adipocytes) and reduced lipotoxicity, which otherwise will be toxic to the heart. More importantly, this review examines the activity of EET in biological systems and a series of pathways that explain its mechanism of action and discusses how these might be exploited for potential therapeutic use. We also discuss the link between cardiac ectopic fat deposition and cardiac function in humans, which is similar to that described in obese mice and is regulated by HO-1-EET-PGC1α signaling, a potent negative regulator of the inflammatory adipokine NOV.

The heme oxygenase system selectively enhances the anti-inflammatory macrophage-M2 phenotype, reduces pericardial adiposity, and ameliorated cardiac injury in diabetic cardiomyopathy in Zucker diabetic fatty rats.

Cardiac function is adversely affected by pericardial adiposity. We investigated the effects of the heme oxygenase (HO) inducer, hemin on pericardial adiposity, macrophage polarization, and diabetic cardiopathy in Zucker diabetic fatty rats (ZDFs) with use of echocardiographic, quantitative real-time polymerase chain reaction, Western immunoblotting, enzyme immunoassay, and spectrophotometric analysis. In ZDFs, hemin administration increased HO activity; normalized glycemia; potentiated insulin signaling by enhancing insulin receptor substrate 1(IRS-1), phosphatidylinositol-3-kinase (PI3K), and protein kinase B (PKB)/Akt; suppressed pericardial adiposity, cardiac hypertrophy, and left ventricular longitudinal muscle fiber thickness, a pathophysiological feature of cardiomyocyte hypertrophy; and correspondingly reduced systolic blood pressure, total peripheral resistance, and pro-inflammatory/oxidative mediators, including nuclear factor κB (NF-κB), cJNK, c-Jun-N-terminal kinase (cJNK), endothelin (ET-1), tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-1ß, activating protein 1 (AP-1), and 8-isoprostane, whereas the HO inhibitor, stannous mesoporphyrin, nullified the effects. Furthermore, hemin reduced the pro-inflammatory macrophage M1 phenotype, but enhanced the M2 phenotype that dampens inflammation. Because NF-κB activates TNFα, IL-6, and IL-1ß and TNF-α, cJNK, and AP-1 impair insulin signaling, the high levels of these cytokines in obesity/diabetes would create a vicious cycle that, together with 8-isoprostane and ET-1, exacerbates cardiac injury, compromising cardiac function. Therefore, the concomitant reduction of pro-inflammatory cytokines and macrophage infiltration coupled to increased expressions of IRS-1, PI3K, and PKB may account for enhanced glucose metabolism and amelioration of cardiac injury and function in diabetic cardiomyopathy. The hemin-induced preferential polarization of macrophages toward anti-inflammatory macrophage M2 phenotype in cardiac tissue with concomitant suppression of pericardial adiposity in ZDFs are novel findings. These data unveil the benefits of hemin against pericardial adiposity, impaired insulin signaling, and diabetic cardiomyopathy and suggest that its multifaceted protective mechanisms include the suppression of inflammatory/oxidative mediators.

Effects of intracoronary delivery of allogenic bone marrow-derived stem cells expressing heme oxygenase-1 on myocardial reperfusion injury.

Heme oxygenase-1 (HO-1) decreases apoptosis, inflammation and oxidative stress. The aim of the study was to investigate the effects of intracoronary infusion of allogenic bone marrow cells (BMC) overexpressing HO-1 in the porcine model of myocardial infarction (MI). MI was produced by balloon occlusion of a coronary artery. BMC were transduced with adenoviruses encoding for HO-1 (HO-1 BMC) or GFP (GFP-BMC) genes. Prior to reperfusion animals received HO-1 BMC, control BMC (unmodified or GFP-BMC) or placebo. Left ventricular (LV) ejection fraction (EF), shortening fraction (SF), end-systolic and end-diastolic diameters (EDD, ESD) were assessed by echocardiography before, 30 minutes (min) and 14 days after reperfusion. BMC significantly improved LVEF and SF early (30 min) after reperfusion as well as after 14 days. Early after reperfusion HO-1 BMC were significantly more effective than control BMC, but after 14 days, there were no differences. There were no effect of cells on LV remodelling and diastolic function. Both HO-1 BMC and control BMC significantly reduced the infarct size vs. placebo (17.2 ± 2.7 and 18.8 ± 2.5, respectively, vs. 27.5 ± 5.1, p= 0.02) in histomorphometry. HO-1-positive donor BMC were detected in the infarct border area in pigs receiving HO-1-cells. No significant differences in expression of inflammatory genes (SDF-1, TNF-α, IL-6, miR21, miR29a and miR133a) in the myocardium were found. In conclusion, intracoronary delivery of allogeneic BMC immediately prior to reperfusion improved the LVEF and reduced the infarct size. HO-1 BMC were not superior to control cells after 14 days, however, produced faster recovery of LVEF. Transplanted cells survived in the peri-infarct zone.

The role of heme oxygenase and carbon monoxide in inflammatory bowel disease.

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease, is a chronic and recurrent inflammatory disorder of the intestinal tract. Since the precise pathogenesis of IBD remains unclear, it is important to investigate the pathogenesis of IBD and to evaluate new anti-inflammatory strategies. Recent evidence suggests that heme oxygenase-1 (HO-1) plays a critical protective role during the development of intestinal inflammation. In fact, it has been demonstrated that the activation of HO-1 may act as an endogenous defensive mechanism to reduce inflammation and tissue injury in various animal intestinal injury models induced by ischemia-reperfusion, indomethacin, lipopolysaccharide-associated sepsis, trinitrobenzene sulfonic acid or dextran sulfate sodium. In addition, carbon monoxide (CO) derived from HO-1 has been shown to be involved in the regulation of intestinal inflammation. Furthermore, administration of a low concentration of exogenous CO has a protective effect against intestinal inflammation. These data suggest that HO-1 and CO may be novel therapeutic molecules for patients with gastrointestinal inflammatory diseases. In this review, we present what is currently known regarding the role of HO-1 and CO in intestinal inflammation.

Effects of heme oxygenase 1 on brain edema and neurologic outcome after cardiopulmonary resuscitation in rats.

BACKGROUND: Heme oxygenase 1 (HO-1) has been shown to attenuate neuronal injury. Therefore, the authors examined whether HO-1 would reduce the brain damage caused by cardiac arrest. METHODS: Rats anesthetized with halothane were subjected to 8 min of cardiac arrest by asphyxia without any pretreatment (control group) or pretreated with an inducer of HO-1 (hemin group) or with an inhibitor of HO-1 (tin protoporphyrin group). Then, the animals were resuscitated with a standardized method. Brain water content (1 and 6 h after resuscitation), neurologic deficit score, viable neuronal counts, and caspase-3 immunostaining in the hippocampus (4 and 14 days) were evaluated. RESULTS: Water content in the hemin group was significantly reduced (mean +/- SD: 83.1 +/- 1.9% for 1 h after resuscitation; P = 0.03) and significantly greater in the tin protoporphyrin group (91.1 +/- 2.0% for 1 h after resuscitation; P = 0.035) when compared with the control group (88.2 +/- 2.4%). Water content of the cortex was nearly the same as that of the hippocampus. Neurologic deficit scores and neuronal survival were significantly better in the hemin group than in the control group on the 4th and 14th days. In rats that survived for 4 days, the amount of caspase 3-positive neurons was 27 +/- 7 in the control group, whereas the value was 14 +/- 6 in the hemin group (P < 0.05). CONCLUSIONS: In rats resuscitated from cardiac arrest, induction of HO-1 by hemin reduced brain edema, improved neurologic outcome, and protected neurons against apoptosis.

Preemptive heme oxygenase-1 gene delivery reveals reduced mortality and preservation of left ventricular function 1 yr after acute myocardial infarction.

We reported previously that predelivery of heme oxygenase-1 (HO-1) gene to the heart by adeno-associated virus-2 (AAV-2) markedly reduces ischemia and reperfusion (I/R)-induced myocardial injury. However, the effect of preemptive HO-1 gene delivery on long-term survival and prevention of postinfarction heart failure has not been determined. We assessed the effect of HO-1 gene delivery on long-term survival, myocardial function, and left ventricular (LV) remodeling 1 yr after myocardial infarction (MI) using echocardiographic imaging, pressure-volume (PV) analysis, and histomorphometric approaches. Two groups of Lewis rats were injected with 2 x 10(11) particles of AAV-LacZ (control) or AAV-human HO-1 (hHO-1) in the anterior-posterior apical region of the LV wall. Six weeks after gene transfer, animals were subjected to 30 min of ischemia by ligation of the left anterior descending artery followed by reperfusion. Echocardiographic measurements and PV analysis of LV function were obtained at 2 wk and 12 mo after I/R. One year after acute MI, mortality was markedly reduced in the HO-1-treated animals compared with the LacZ-treated animals. PV analysis demonstrated significantly enhanced LV developed pressure, elevated maximal dP/dt, and lower end-diastolic volume in the HO-1 animals compared with the LacZ animals. Echocardiography showed a larger apical anterior-to-posterior wall ratio in HO-1 animals compared with LacZ animals. Morphometric analysis revealed extensive myocardial scarring and fibrosis in the infarcted LV area of LacZ animals, which was reduced by 62% in HO-1 animals. These results suggest that preemptive HO-1 gene delivery may be useful as a therapeutic strategy to reduce post-MI LV remodeling and heart failure.

Adenovirus-mediated transfer and overexpression of heme oxygenase 1 cDNA in lungs attenuates elastase-induced pulmonary emphysema in mice.

Heme oxygenase 1 (HO-1) is an inducible enzyme that catalyzes heme to generate bilirubin, ferritin, and carbon monoxide. Because enhanced expression of HO-1 provides an anti-inflammatory effect and confers cytoprotection, we examined whether HO-1 overexpression induced by inoculation of mice with an adenovirus encoding HO-1 (Ad.HO-1) in the lung would prevent pulmonary emphysema induced by porcine pancreatic elastase (PPE). Pretreatment with Ad.HO-1, which upregulated production of HO-1 in the lung, attenuated the PPE-induced increase of neutrophils in bronchoalveolar lavage fluid (BALF) and enlargement of alveoli. It also reduced PPE-induced elevated levels of tumor necrosis factor alpha, interleukin (IL)-6, and keratinocyte-derived chemokine, and increased the level of anti-inflammatory cytokine IL-10 in BALF. These results suggest that Ad.HO-1-induced HO-1 overexpression suppressed PPE-induced emphysema by attenuating neutrophilic inflammation via modulating cytokine and chemokine profiles in mouse lungs.

Heme oxygenase-1: a new therapeutic target for inflammatory bowel disease.

Heme oxygenase (HO) is the rate-limiting enzyme in the catabolism of heme, followed by production of biliverdin, free iron and carbon monoxide (CO). Three mammalian HO isozymes have been identified, one of which, HO-1, is a stress-responsive protein induced by various oxidative agents. HO-2 and HO-3 genes are constitutively expressed. Recent studies demonstrate that the expression of HO-1 in response to different inflammatory mediators may contribute to the resolution of inflammation and have 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 intestinal 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 trinitrobenzene sulphonic acid or dextran sulphate sodium, indicating that activation of HO-1 may act as an endogenous defensive mechanism to reduce inflammation and tissue injury in the intestinal tract. These in vitro and in vivo data suggest that HO-1 may be a novel therapeutic target in patients with inflammatory bowel disease.

Hemoglobin-based red blood cell substitutes.

Polyhemoglobin is already well into the final stages of clinical trials in humans with one approved for routine clinical use in South Africa. Conjugated hemoglobin is also in ongoing clinical trials. Meanwhile, recombinant Hb has been modified to modulate the effects of nitric oxide. Other systems contain antioxidant enzymes for those clinical applications that may have potential problems related to ischemia-reperfusion injuries. Other developments are based on hemoglobin-lipid vesicles and also the use of nanotechnology and biodegradable copolymers to prepare nanodimension artificial red blood cells containing hemoglobin and complex enzyme systems.

O papel da heme oxigenase-1 na lesão celular desencadeada pelo sulfato de polimixina B em células LLC-PK1 / The role of heme oxygenase-1 in the cellular injury caused by polymyxin B sulphate on LLC-PK1 cells

A heme-oxigenase-1 (HO-1) é uma enzima induzível envolvida na degradação do grupo prostético heme, produzindo compostos com funções anti-oxidante, anti-inflamatória, anti-apoptótica e modulatória do sistema imune no rim. A importância de sua indução está associada à resposta adaptativa ao estresse oxidativo e à inflamação envolvidos na gênese da insuficiência renal aguda. O sulfato de polimixina B é um antibiótico usado no tratamento de infecções Gram-negativas e que apresenta um efeito nefrotóxico ainda não completamente elucidado. O objetivo deste estudo foi verificar a viabilidade e apoptose de células LLC-PK1 submetidas ao tratamento com polimixina B, com tempos de exposição diferentes, e pré-tratadas com hemin (indutor de heme oxigenase-1) ou protoporfirina de zinco (inibidor de heme oxigenase-1). Células renais de porco, LLC-PK1, foram cultivadas com polimixina B durante 24, 48 e 72 horas. A apoptose e viabilidade celular foram avaliadas usando diferentes doses do antibiótico: Controle (CTL, 0 µM); G1 (12,5µM); G2 (37,5µM); G3 (75µM); G4 (125µM) e G5 (375µM). O hemin (25µM) e a protoporfirina de zinco (10µM) foram administrados uma hora antes da polimixina B. Foram utilizados os métodos Acridine orange/ brometo de etídio (viabilidade) e Hoescht 33342 (apoptose). Os resultados demonstraram redução linear de viabilidade induzida pela polimixina B quando a dose e o tempo de exposição foram aumentados, isto foi confirmado pela variação inversa de apoptose. O hemin aumentou a viabilidade e reduziu apoptose na presença de polimixina B, sugerindo um efeito protetor da HO-1 neste modelo. O efeito observado para a protoporfirina de zinco foi semelhante ao descrito para o hemin. O estudo confirmou a citotoxicidade da polimixina B em células renais e constatou que esse efeito pode ser mediado pela HO-1 considerando o efeito obtido no tratamento com o indutor daquela enzima

Therapeutic applications of human heme oxygenase gene transfer and gene therapy.

The search for methods to control physiological levels of carbon monoxide (CO), a vasoactive molecule, and bilibrubin, an antioxidant, have improved our understanding of the protective role of heme oxygenase (HO) against oxidative injury. HO activity can assist other antioxidant systems in diminishing the overall production of reactive oxygen species, thus contributing to cellular resistance to such injury. Overexpression of HO gene by targeted gene transfer has become a powerful tool for studying the role of this human enzyme. Successful and functional HO gene transfer requires two essential elements. First, the HO gene must be delivered into a safe vector, such as the adenoviral, retroviral and leptosome based vectors that are currently being used in clinical trials. The use of non-viral vectors has also been described. Second, with the exception of HO gene delivery to ocular or cardiovascular tissue via catheter-based interventions, HO gene delivery must be site and organ specific. Site-specific delivery of HO-1 to renal structures in SHR, specifically mTAL, using Na+-K+ Cl- cotransporter (NKCC2 promoter), has been shown to normalize blood pressure and provide protection to mTAL against oxidative injury, respectively. Human HO-1 gene transfer into endothelial cells has been shown to attenuate Ang II- TNF- and heme-mediated DNA damage. Furthermore, delivery of human HO-1 into SHR has been shown to enhance somatic body growth and cell proliferation. The ability to transfect human HO gene and to demonstrate its expression may offer a new therapeutic strategy for treating pathological conditions, such as hypertension, trauma and hemorrhage.

Protective role of heme oxygenase-1 induction in carbon tetrachloride-induced hepatotoxicity.

Reductive metabolism of carbon tetrachloride (CCl(4)) is thought to cause lipid peroxidation which results in hepatic injury. Heme oxygenase-1 (HO-1) (EC 1.14.99.3), the rate-limiting enzyme in heme catabolism, is known to be induced by oxidative stress and to confer protection against oxidative tissue injuries. In this study, we examined the role of HO-1 induction in a rat model of CCl(4)-induced acute liver injury. CCl(4) treatment (1 mL/kg, intraperitoneally) produced severe hepatic injury in rats as revealed by significant increases in serum alanine transaminase (ALT) (EC 2.6.1.2) activity and hepatic malondialdehyde (MDA) content, severe liver cell injury, and increases in hepatic tumor necrosis factor-alpha (TNF-alpha) mRNA expression and DNA binding activity of nuclear factor-kappa B (NF-kappa B). Following CCl(4) treatment, hepatic HO-1 expression was markedly increased both at transcriptional and protein levels in hepatocytes, especially around the central vein. HO-1 induction was mediated in part through a rapid increase in microsomal free heme concentration presumably derived from hepatic cytochrome P450. Inhibition of HO activity by tin-mesoporphyrin (Sn-MP), which resulted in a sustained increase in microsomal free heme concentration, exacerbated liver injury, as judged by the sustained increase in serum ALT activity, extensive hepatocytes injuries, a more pronounced expression of hepatic TNF-alpha mRNA and an enhanced NF-kappa B activation. These findings indicate that induction of HO-1 is an adaptive response to CCl(4) treatment, and it may be critical in the recovery of hepatocytes from injury. Our findings also suggest that HO-1 induction may play an important role in conferring protection on hepatocytes from oxidative damage caused by free heme.

Heme oxygenase-1 system in organ transplantation.

The heme oxygenase-1 (HO-1) system, the rate-limiting step in the conversion of heme, is among the most critical of cytoprotective mechanisms activated during cellular stress. The cytoprotection may result from the elimination of heme and the function of HO-1 downstream mediators, that is, biliverdin, carbon monoxide, and free iron. HO-1 overexpression exerts beneficial effects in a number of transplantation models, including antigen-independent ischemia/reperfusion injury, acute and chronic allograft rejection, and xenotransplantation. The HO-1 system is thought to exert four major functions: (1) antioxidant function; (2) maintenance of microcirculation; (3) modulatory function upon the cell cycle; and (4) anti-inflammatory function. The antioxidant function depends on heme degradation, oxygen consumption, biliverdin, and production of ferritin via iron accumulation. The production of carbon monoxide, which has vasodilation and antiplatelet aggregation properties, maintains tissue microcirculation and may be instrumental in antiapoptotic and cell arrest mechanisms. Heme catabolism and HO-1 overexpression exert profound direct and indirect inhibitory effects on the cascade of host inflammatory responses mediated by neutrophils, macrophages, and lymphocytes. These anti-inflammatory properties result in cytoprotection in a broad spectrum of graft injury experimental models, including ischemia/reperfusion, acute and chronic allograft, and xenotransplant rejection. Further, the multifaceted targets of HO-1-mediated cytoprotection may simultaneously benefit both local graft function and host systemic immune responses. Thus, the HO-1 system serves as a novel therapeutic concept in organ transplantation.

Heme oxygenase-1 gene therapy for prevention of vasospasm in rats.

OBJECT: Hemoglobin causes contraction of cerebral arteries and is also believed to cause vasospasm after subarachnoid hemorrhage (SAH). The goal in this study was to determine if overexpression of heme oxygenase-1 (HO-1), the principal enzyme involved in the metabolism of hemoglobin, would reduce contractions of cerebral arteries brought on by hemoglobin and decrease vasospasm after experimental SAH. METHODS: Injection of adenovirus expressing HO-1 (Ad5HO-1) into the cisterna magna of rats produced a significant increase in expression of HO-1 messenger RNA, and protein and HO-1 activity in the basilar artery ([BA]; p < 0.05 for each measure compared with vehicle and/or control virus, according to analysis of variance or unpaired t-test). Injection of adenovirus expressing beta-galactosidase (Ad-betaGal) produced only mild, statistically nonsignificant increases. The HO-I immunoreactivity was localized to the BA adventitia after injection of Ad5HO-1 or Ad-betaGal. Injection of Ad5HO-1 and Ad-betaGal increased the baseline diameter of the BA (measured directly via a transclival window) and brainstem cerebral blood flow (CBF), measured by laser Doppler flowmetry, compared with vehicle. Contraction of the BA after addition of hemoglobin was significantly inhibited, reduction in brainstem CBF was significantly prevented, and carboxyhemoglobin concentration was significantly increased in rats injected with Ad5HO-1 compared with Ad-betaGal and vehicle. Vasospasm was significantly ameliorated in rats in which Ad5HO-1 was injected into the cisterna magna at the time of SAH in a double-hemorrhage model. CONCLUSIONS: These results show that overexpression of HO-1 inhibits arterial contractions induced by hemoglobin and can reduce vasospasm after experimental SAH.

Heme oxygenase-1 as a protective gene.

Heme oxygenases catalyze the rate-limiting step in heme degradation, resulting in the formation of carbon monoxide, iron and biliverdin that is subsequently reduced to bilirubin by biliverdin reductase. The products of this enzymatic reaction have important biological effects, including antioxidant, anti-inflammatory and cytoprotective functions. Three isoforms of heme oxygenase (HO) have been described: two constitutively expressed isoforms, HO-2 and HO-3, and an inducible isoform, HO-1 that is increased as an adaptive response to several injurious stimuli including heme, hyperoxia, hypoxia, endotoxin and heavy metals. Induction of HO-1 has been implicated in numerous clinically relevant disease states including transplant rejection, hypertension, atherosclerosis, lung injury, endotoxic shock and others. This review will focus on the protective functions of HO-1.

Induction of heme-oxygenase-1 prevents the systemic responses to hemorrhagic shock.

Oxidant-mediated reperfusion injury of the gut is a major contributor of the systemic inflammatory response in hemorrhagic shock. Recent studies have suggested that heme-oxygenase-1 (HO-1) represents an endogenous protective mechanism against oxidant stress. We assessed whether HO-1 induction modulates the synthesis of tumor necrosis factor-alpha (TNF-alpha) in hemorrhagic shock. In rats submitted to hemorrhagic shock, pretreatment with hemoglobin (Hb) increased HO-1 mRNA expression in macrophages. This increased expression was associated with a decreased expression of TNF-alpha mRNA, as well as decreased plasma concentrations of TNF-alpha. These effects of Hb were reduced by the HO-1 inhibitor tin-protoporphyrin (Sn-PP 20 micromol/kg), while Sn-PP had no effect in the absence of Hb. In parallel, Hb pretreatment reduced pulmonary edema, vascular injury, and increased mesenteric blood flow, and these effects were reduced by Sn-PP. Thus, induction of HO-1 is protective in hemorrhagic shock, possibly through its antioxidant properties. Interventions that induce HO-1 may be beneficial in the treatment of shock states, leading to a reduced systemic inflammatory response.

[Ischemia-reperfusion]. / Ischémie-reperfusion.

IMPORTANCE OF ISCHEMIA-REPERFUSION LESIONS: After transplantation, ischemia-reperfusion lesions are associated with an increased risk of acute rejection, late recovery of liver function, or chronic graft dysfunction. In all, about 20% of the grafts are lost. The importance of prevention is evident. HEME-OXYGENASE: It has been shown that heme-oxygenase, an anti-oxidant reducing apoptosis, reduces the extent of ischemia-reperfusion lesions after liver, heart, kidney or Langerhans islet transplantation. OTHER COMPOUNDS WITH INTERESTING PROPERTIES: Other compounds also have interesting properties for preventing ischemia-reperfusion lesions: a specific metallo-protease inhibitor, L-arginine, a selective agonist of the PGE1 receptor, estrogens, low-dose cyclosporine, and certain immunosuppressors (FTY 720, anti CD28, anti B7-1), and rPSGL-Ig ligand.