Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heme oxygenase (HO) catalyzes the oxidative cleavage of the alpha-mesocarbon of Fe-protoporphyrin-IX yielding equimolar amounts of biliverdin-IXalpha, free divalent iron, and carbon monoxide (CO). Among the three isoenzymes cloned to date, only HO-1 can be induced by a variety of seemingly disparate stimuli, most of which are linked by their ability to provoke oxidative stress. Although constitutive expression of HO-1 in the liver is restricted to Kupffer cells, the gene is inducible in nonparenchymal as well as in parenchymal liver cells. HO-1 induction potentially confers protection against oxidative stress in a variety of experimental models, such as liver ischemia/reperfusion secondary to transplantation or hemorrhage/resuscitation. Induction of HO-1 may protect the cell against oxidative injury by (a) controlling intracellular levels of "free" heme (a prooxidant), (b) producing biliverdin (an antioxidant), (c) improving nutritive perfusion via CO release, and (d) fostering the synthesis of the Fe-binding protein ferritin. Although protective effects of up-regulation of the HO pathway--presumably through production of bile pigments and CO--have been reported for a variety of cells and tissues, including the liver, evidence suggests that the protective action might be restricted to a rather narrow threshold of overexpression. High levels of HO-1 may even sensitize the cell to oxidative stress, e.g., through release of reactive iron. Transcriptional activation of the HO-1 gene is an integral part of the cellular response to oxidative stress, but its induction seems to be neither exclusively cytoprotective nor exclusively cytotoxic.
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PMID:Heme oxygenase-1: redox regulation and role in the hepatic response to oxidative stress. 1247 May 2

Heme oxygenase-1 (HO1) catalyzes oxidation of the heme molecule in concert with NADPH-cytochrome P450 reductase following the specific cleavage of heme into carbon monoxide, iron, and biliverdin, which is rapidly metabolized to bilirubin. HO1 is a stress-inducible protein that protects cells against oxidative injury, but its protective mechanism is not fully understood. The Eizai hyperbilirubinemic rat (EHBR), a mutant strain derived from the Sprague-Dawley rat (SDR), has a mutation in the gene for the canalicular multispecific organic anion transporter, which results in a phenotype of hyperbilirubinemia, and thus is a model of Dubin-Johnson syndrome in humans. In this study, we compared EHBR and SDR with regard to neuronal death induced by 2 hr of occlusion of the middle cerebral artery and reperfusion. In EHBR, the area that was immunoreactive for microtubule-associated protein-2 was significantly reduced, and the HO1-immunoreactive area was smaller than that in SDR. These results suggest that bilirubin has essentially a neuroprotective effect against focal ischemia and may participate in HO1-induced neuroprotection.
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PMID:Hyperbilirubinemia protects against focal ischemia in rats. 1254 10

Heme oxygenase-1 (HO-1) overexpression using gene transfer protects rat livers against ischemia/reperfusion (I/R) injury. This study evaluates the effects of Ad-HO-1 gene transfer in a rat renal isograft model. Donor LEW kidneys were perfused with Ad-HO-1, Ad-beta-gal, or PBS, stored at 4 degrees C for 24 h, and transplanted orthotopically into LEW recipients, followed by contralateral native nephrectomy. Serum creatinine, urine protein/creatinine ratios, severity of histologic changes, HO-1 mRNA/protein expression, and HO enzymatic activity were analyzed. Ad-HO-1 gene transfer conferred a survival advantage when compared with PBS- and Ad-beta-gal-treated controls, with median survival of 100, 7, and 7 d, respectively (P < 0.01). Serum creatinine levels were elevated at day 7 in all groups (range, 2.2 to 5.8 mg/dl) but recovered to 1.0 mg/dl by day 14 (P < 0.01) in Ad-HO-1 group, which was sustained thereafter. Urine protein/creatinine ratio at day 7 was elevated in both PBS and Ad-beta-gal, as compared with the Ad-HO-1 group (12.0 and 9.8 versus 5.0; P < 0.005); histologically, ATN and glomerulosclerosis was more severe in Ad-beta-gal group at all time points. Reverse transcriptase-PCR-based HO-1 gene expression was significantly increased before reperfusion (P < 0.001) and remained increased in the Ad-HO-1-treated group for 3 d after transplantation. Concomitantly, HO enzymatic activity was increased at transplantation and at 3 d posttransplant in the Ad-HO-1 group, compared with Ad-beta-gal controls (P < 0.05); tubular HO-1 expression was discernible early posttransplant in the Ad-HO-1 group alone. These findings are consistent with protective effects of HO-1 overexpression using a gene transfer approach against severe renal I/R injury, with reduced mortality and attenuation of tissue injury.
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PMID:Gene transfer-induced local heme oxygenase-1 overexpression protects rat kidney transplants from ischemia/reperfusion injury. 1259 12

Heme oxygenase (HO) is a cytoprotective enzyme that degrades heme (a potent oxidant) to generate carbon monoxide (a vasodilatory gas that has anti-inflammatory properties), bilirubin (an antioxidant derived from biliverdin), and iron (sequestered by ferritin). Because of the properties of inducible HO (HO-1) and its products, we hypothesized that HO-1 would play an important role in the regulation of cardiovascular function. In this article, we will review the role of HO-1 in the regulation of blood pressure and cardiac function and highlight previous studies from our laboratory using gene deletion and gene overexpression transgenic approaches in mice. These studies will include the investigation of HO-1 in the setting of hypertension (renovascular), hypotension (endotoxemia), and ischemia/reperfusion injury (heart). In a chronic renovascular hypertension model, hypertension, cardiac hypertrophy, acute renal failure, and acute mortality induced by one kidney-one clip surgery were more severe in HO-1-null mice. In addition, HO-1-null mice with endotoxemia had earlier resolution of hypotension, yet the mortality and the incidence of end-organ damage were higher in the absence of HO-1. In contrast, mice with cardiac-specific overexpression of HO-1 had an improvement in cardiac function, smaller myocardial infarctions, and reduced inflammatory and oxidative damage after coronary artery ligation and reperfusion. Taken together, these studies suggest that an absence of HO-1 has detrimental consequences, whereas overexpression of HO-1 plays a protective role in hypoperfusion and ischemia/reperfusion injury.
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PMID:Role of heme oxygenase-1 in the regulation of blood pressure and cardiac function. 1270 67

Heme oxygenase (HO) produced biliverdin and bilirubin, which are powerful antioxidants, therefore, it has been proposed as helpful against oxidative stress. In contrast, HO also produces iron, and it could increase oxidative stress if not handled property. To clarify the effect of HO, i.e., helpful or harmful, we examined the expression, localization, and induction mechanism of HO-1 in the rat hippocampus after transient forebrain ischemia and injection of kainic acid (KA). Following ischemia, HO-1 expression was observed early but transiently in the CA1 pyramidal neurons and later but continuously in glial cells. In addition, HO-1-expressing pyramidal neurons were colocalized well with phosphorylated c-Jun, which is a critical step in neuronal apoptosis. After injection of KA, HO-1 expression was observed only in glial cells but not neurons, and HO-1 expression was observed in predominantly ameboid microglia, along with a few astrocytes. HO-1-expressing ameboid microglia expressed major histocompatibility complex class II antigen, suggesting strong activation. These results suggested that HO-1 may have double-edged effects, and its effects may be depend on the cell type. This short review is intended to highlight on the effect of HO-1 in neurodegeneration.
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PMID:Induction of inducible heme oxygenase (HO-1) in the central nervous system: is HO-1 helpful or harmful? 1283 7

Polyphenolic compounds, such as resveratrol, are naturally present at high concentration in grape skin, seeds, and red wine. Resveratrol is present in cis and trans isoforms and the major trans isomer is the biologically active one. Epidemiologic studies have revealed a reduced incidence of cardiovascular risk associated with consumers of red wine; this has been popularized as the French paradox. Resveratrol has been shown to have significant antioxidant properties in a variety of in vitro and in vivo models. It can reduce ischemic damage in heart ischemia reperfusion injury and also in brain ischemia/reperfusion in rodent models. Due to the high rate of oxygen consumption in the brain, and especially low levels of antioxidant defense enzymes, this organ is particularly susceptible of free radical damage. Most of the protective biological actions associated with resveratrol have been associated with its intrinsic radical scavenger properties. We have investigated the possibility of other indirect pathways by which resveratrol can exert its neuroprotective abilities. We have specifically tested whether heme oxygenase neuroprotective enzyme could be stimulated after resveratrol treatment. Using primary neuronal cultures, resveratrol was able to significantly induce heme oxygenase 1, whereas vehicle control showed no effect. No detectable toxicity was quantified. It is well established that after stroke significant levels of intracellular heme levels increase. The source of free heme comes mainly from several heme-containing enzymes. Heme (iron-protoporphyrin IX) is a pro-oxidant and its rapid degradation by heme oxygenase is believed to be protective. Moreover, the generation of heme metabolites can also have their own intrinsic cellular properties. All together, increased heme oxygenase activity by resveratrol is a unique pathway by which this compound can exert its neuroprotective actions.
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PMID:Potential mechanism by which resveratrol, a red wine constituent, protects neurons. 1285 18

Heme oxygenase (HO)-1 catabolizes heme into three products: carbon monoxide (CO), biliverdin (which is rapidly converted to bilirubin) and free iron (which leads to the induction of ferritin, an iron-binding protein). HO-1 serves as a "protective" gene by virtue of the anti-inflammatory, anti-apoptotic and anti-proliferative actions of one or more of these three products. Administration of CO, biliverdin, bilirubin or iron-binding compounds is protective in rodent disease models of ischemia-reperfusion injury, allograft and xenograft survival, intimal hyperplasia following balloon injury or as seen in chronic graft rejection and others. We suggest that the products of HO-1 action could be valuable therapeutic agents and speculate that HO-1 functions as a "therapeutic funnel", mediating the beneficial effects attributed to other molecules, such as interleukin-10 (IL-10), inducible nitric oxide synthase (NOS2; iNOS) and prostaglandins. This Review is the third in a series on the regulation of the immune system by metabolic pathways.
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PMID:Heme oxygenase-1: unleashing the protective properties of heme. 1290 59

Heme oxygenase-1 (HO-1)-dependent carbon monoxide (CO) production related to reperfusion-induced ventricular fibrillation (VF) was studied in HO-1 wild-type (+/+), heterozygous (+/-), and homozygous (-/-) isolated ischemic/reperfused mouse heart. In HO-1 homozygous myocardium, under aerobic conditions, HO-1 enzyme activity, HO-1 mRNA, and protein expression were not detected in comparison with aerobically perfused wild-type and heterozygous myocardium. In wild-type, HO-1 hetero- and homozygous hearts subjected to 20 min ischemia followed by 2 h of reperfusion, the expression of HO-1 mRNA, protein, and HO-1 enzyme activity was detected in various degrees. A reduction in the expression of HO-1 mRNA, protein, and enzyme activity in fibrillated wild-type and heterozygous myocardium was observed. In reperfused/nonfibrillated wild-type and heterozygous hearts, a reduction in HO-1 mRNA, protein expression, and HO-1 enzyme activity was not observed, indicating that changes in HO-1 mRNA, protein, and enzyme activity could be related to the development of VF. These changes were reflected in the HO-1-related endogenous CO production measured by gas chromatography. In HO-1 knockout ischemic/reperfused myocardium, all hearts showed VF, and no detection in HO-1 mRNA, protein, and enzyme activity was observed. Thus, interventions that are able to increase endogenous CO may prevent the development of VF.
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PMID:Heme oxygenase-1-related carbon monoxide production and ventricular fibrillation in isolated ischemic/reperfused mouse myocardium. 1295 58

Heme oxygenase-1 (HO-1) is induced under a variety of pro-oxidant conditions such as those associated with ischemia-reperfusion injury (IRI) of transplanted organs. HO-1 cleaves the heme porphyrin ring releasing Fe2+, which induces the expression of the Fe2+ sequestering protein ferritin. By limiting the ability of Fe2+ to participate in the generation of free radicals through the Fenton reaction, ferritin acts as an anti-oxidant. We have previously shown that HO-1 protects transplanted organs from IRI. We have linked this protective effect with the anti-apoptotic action of HO-1. Whether the iron-binding properties of ferritin contributed to the protective effect of HO-1 was not clear. We now report that recombinant adenovirus mediated overexpression of the ferritin heavy chain (H-ferritin) gene protects rat livers from IRI and prevents hepatocellular damage upon transplantation into syngeneic recipients. The protective effect of H-ferritin is associated with the inhibition of endothelial cell and hepatocyte apoptosis in vivo. H-ferritin protects cultured endothelial cells from apoptosis induced by a variety of stimuli. These findings unveil the anti-apoptotic function of H-ferritin and suggest that H-ferritin can be used in a therapeutic manner to prevent liver IRI and thus maximize the organ donor pool used for transplantation.
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PMID:Heavy chain ferritin acts as an antiapoptotic gene that protects livers from ischemia reperfusion injury. 1295 89

Heme oxygenase-1 (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 injury and rejection. Here we investigated the protective potential of HO-1 in 5 models of immune-mediated liver injury. We found that up-regulation of endogenous HO-1 by cobalt-protoporphyrin-IX (CoPP) protected mice from apoptotic liver damage induced by anti-CD95 antibody (Ab) or d-galactosamine in combination with either anti-CD3 Ab, lipopolysaccharide (LPS), or tumor necrosis factor alpha (TNF-alpha). HO-1 induction prevented apoptotic liver injury, measured by inhibition of caspase 3 activation, although it did not protect mice from caspase-3-independent necrotic liver damage caused by concanavalin A (Con A) administration. In addition, overexpression of HO-1 by adenoviral gene transfer resulted in protection from apoptotic liver injury, whereas inhibition of HO-1 enzymatic activity by tin-protoporphyrin-IX (SnPP) abrogated the protective effect. HO-1-mediated protection seems to target parenchymal liver cells directly because CoPP treatment protected isolated primary hepatocytes from anti-CD95-induced apoptosis in vitro. Furthermore, depletion of Kupffer cells (KCs) did not interfere with the protective effect in vivo. Exogenous CO administration or treatment with the CO-releasing agent methylene chloride mimicked the protective effect of HO-1, whereas treatment with exogenous biliverdin or overexpression of ferritin by recombinant adenoviral gene transfer did not. In conclusion, HO-1 is a potent protective factor for cytokine- and CD95-mediated apoptotic liver damage. Induction of HO-1 might be of a therapeutic modality for inflammatory liver diseases.
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PMID:Heme oxygenase-1 and its reaction product, carbon monoxide, prevent inflammation-related apoptotic liver damage in mice. 1572 11


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