UMLS:C0022116 - FACTA Search

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carbon monoxide (CO) is an endogenously generated gas that may play an important physiological role in the circulation. CO is generated by vascular cells as a byproduct of heme catabolism, in which heme oxygenase (HO) catalyzes the degradation of heme to biliverdin, iron and CO. Two distinct isoforms of HO have been identified in vascular tissue. The HO-2 isoform is constitutively expressed and likely mediates the release of CO under normal physiologic conditions. In contrast, the HO-1 isoform is strongly induced in vascular cells by various stress-associated agents and markedly increases CO synthesis during pathological conditions. The release of CO by vascular cells exerts both paracrine and autocrine effects on vascular smooth muscle cells (SMC) and circulating blood cells. CO regulates blood flow and blood fluidity by inhibiting vasomotor tone, SMC proliferation, and platelet aggregation. These vascular effects of CO are mediated via the activation of soluble guanylate cyclase and the consequent rise in intracellular guanosine 3',5'-cyclic monophosphate levels in target tissues. CO may also play a role in various cardiovascular disorders, including endotoxin shock, ischemia-reperfusion, hypertension, and subarachnoid hemorrhage. This review will focus on the recent progress made in understanding the regulation and function of CO in the vasculature.
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PMID:Carbon monoxide and vascular cell function (review). 985 96

Heme oxygenase-1 (HO-1, HSP32) is an early gene that is responsive to an array of pathological conditions including, but not limited to, hypoxia and cerebral ischemia. HO-1 cleaves the heme molecule and produces carbon monoxide (CO) and biliverdin (an antioxidant) and is essential for iron homeostasis. The purpose of this study was to investigate, using transgenic (Tg) mice, whether overexpression of HO-1 in the brain augments or attenuates cellular injury caused by ischemic stroke. Homozygous HO-1 Tg mice that overexpress HO-1 under the control of the neuron-specific enolase promoter (characterized previously) were used. Under halothane anesthesia and normothermic conditions, wild-type nontransgenic (nTg; n = 22) and HO-1 Tg (n = 24) mice were subjected to middle cerebral artery occlusion (MCAo). Six hours after induction of ischemia, Tg and nTg mice developed infarcts that were 39 +/- 6 and 63 +/- 9 mm3, respectively (p < 0.01). No significant difference between the two strains was observed in the values of brain edema (11.3 +/- 4% in Tg vs. 14.6 +/- 5% in nTg; p < 0.1). At 24 h after MCAo, Tg mice exhibited significant neuroprotection as determined by the stroke volumes (41 +/- 2 mm3 in Tg vs. 74 +/- 5 mm3 in nTg; p < 0.01) and values of ischemic cerebral edema (21 +/- 6% in Tg vs. 35 +/- 11% in nTg; p < 0.01). Data suggest that neuroprotection in Tg mice was, at least in part, related to the following findings: (a) constitutively up-regulated cyclic GMP and bcl-2 levels in neurons; (b) inhibition of nuclear localization of p53 protein; and (c) antioxidant action of HO-1, as detected by postischemic neuronal expression of ferritin, and decreases in iron staining and tissue lipid peroxidation. We suggest that pharmacological stimulation of HO-1 activity may constitute a novel therapeutic approach in the amelioration of ischemic injury during the acute period of stroke.
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PMID:Overexpression of heme oxygenase-1 is neuroprotective in a model of permanent middle cerebral artery occlusion in transgenic mice. 1003 92

We investigated whether the expression of heme oxygenase (HO) isozymes was related to the occurrence of ventricular fibrillation (VF) induced by ischemia/reperfusion in nondiabetic and diabetic myocardium. To study the role of HO-1 and HO-2 mRNA expression in VF, isolated hearts obtained from nondiabetic and 8-week diabetic rats were subjected to 30 min of ischemia followed by 2 h of reperfusion. Expression of HO-1 and HO-2 mRNA was studied in fibrillated and nonfibrillated myocardium using Northern blotting and reverse transcription polymerase chain reaction (RT-PCR). The effect of zinc protoporphyrin IX (Zn-PPIX), a potent inhibitor of HO activity, on HO activity was also studied in ischemic/reperfused hearts. Upon reperfusion, an expression of HO-1 was observed in nonfibrillated myocardium. HO-1 mRNA expression was significantly reduced in hearts showed VF. Zn-PPIX (5 microM) treatment reduced HO activity from its control values of 398+/-27 (in nondiabetics) and 370+/-20 pmol bilirubin/h (in diabetics) to 69+/-14 (in nondiabetics, p<.05) and 60+/-11 pmol bilirubin/h (in diabetics, p<.05), respectively, and all hearts, upon reperfusion, showed VF in both nondiabetic and diabetic subjects. HO-2 expression was unchanged in nonfibrillated and fibrillated myocardium. Postischemic function showed no correlation with the expression of these genes. Our data show that the mechanism(s) of ischemia/reperfusion-induced VF involves the downregulation of HO-1 mRNA and a reduction in HO activity. Furthermore, the mechanism(s) of VF at molecular level involving HO isozymes does not show a significant difference between nondiabetics and diabetics.
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PMID:Heme oxygenase and cardiac function in ischemic/reperfused rat hearts. 1044 28

Myocardial adaptation to ischemia involves up-regulated expression of a number of genes implicated in conferring cytoprotection. We have previously shown that myocardial ischemia followed by reperfusion leads to a co-ordinated expression of mRNAs encoding heme oxygenase-1 (HO-1) and ubiquitin in pigs. HO-1 participates in biological reaction leading to the formation of the antioxidant, bilirubin and the putative cellular messenger, carbon monoxide. In the present study, we examined the expression and cellular localization of HO-1 in the heart during myocardial stunning in anesthetized pigs. After thoracotomy, the LAD was occluded for 10 min and reperfused for 30 min (group I, n = 4), again occluded for 10 min and reperfused for 30 min (group II, n = 6), 90 min (group III, n = 4), 210 min (group IV, n = 5) and for 390 min (group V, n = 4). Myocardial tissue specimens were collected in 10% formalin as well as in liquid nitrogen and processed for immunohistochemistry and mRNA expression analysis, respectively. In the distribution territory of the LAD (experimental, E), systolic wall thickening was significantly decreased (39 +/- 6%) as compared to that of the area perfused by left circumflex coronary artery (LCx, control) in group I and remained depressed in all subsequent groups. Northern blot analysis revealed that the expression of a single mRNA species of 1.8 kb encoding HO-1 was significantly induced in E as compared to control in groups II and III with maximum mRNA levels in group II (1.9 +/- 0.4 fold vs. control). Immunoreactive HO-1 was localized in the cytoplasm of cardiomyocytes as well as in the perivascular regions in all groups. Semiquantitative analysis of HO-1 staining showed significantly enhanced levels of HO-1 in perivascular region in E as compared to respective controls derived from groups III and IV. These results suggest that myocardial adaptive response to ischemia involves up-regulation of HO-1 in cells of perivascular region indicating that this enzyme may participate in regulating vascular tone via CO and thereby, contributing in pathophysiologically important defense mechanism(s) in the heart.
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PMID:Enhanced expression and localization of heme oxygenase-1 during recovery phase of porcine stunned myocardium. 1044 12

This study aimed to examine whether an elevated activity of heme oxygenase (HO)-1 in the tissue attenuates endothelial cell-leukocyte interactions microvessels in vivo. When rats were pretreated with an intraperitoneal injection of hemin, an HO-1 inducer, mesenteric tissues, including their microvessels, displayed a marked induction of HO-1 concurrent with an increase in plasma concentrations of bilirubin-IXalpha, the product of HO-catalyzed degradation of protoheme IX. In these rats, oxidative stress such as superfusion with H(2)O(2) and ischemia-reperfusion of the tissues neither induced rolling nor exhibited adherent responses of leukocytes in venules. In contrast, the oxidative stresses evoked marked rolling and adhesion of leukocytes in the control rats without HO-1 induction. The HO-1 induction also downregulated leukocyte adhesion elicited by other pro-oxidant stimuli such as N(omega)-nitro-L-arginine methyl ester. The decreases in the oxidant-elicited leukocyte adhesive responses under HO-1-inducing conditions were restored by perfusion with zinc protoporphyrin-IX, an HO inhibitor, but not with copper protoporphyrin-IX, which did not inhibit the enzyme. Furthermore, the effects of zinc protoporphyrin-IX were repressed by superfusion with bilirubin or biliverdin at the micromolar level, but not by the same concentration of carbon monoxide, another product of HO. These results indicate that induction of the HO-1 activity serves as a potential stratagem to prevent oxidant-induced microvascular leukocyte adhesion through the action of bilirubin, a product of HO reaction.
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PMID:Induction of heme oxygenase-1 suppresses venular leukocyte adhesion elicited by oxidative stress: role of bilirubin generated by the enzyme. 1052 Dec 39

In mammals the rate-limiting step in heme catabolism is the heme oxygenase (HO) system. Two isozymes, HO-1 and HO-2, oxidatively cleave the substrate to form biliverdin, and the potential cellular messenger, CO; the chelated iron is released as the result of the tetrapyrrole ring opening. Biliverdin is subsequently reduced to bilirubin, an antioxidant, by biliverdin reductase. The aim of the present study was to investigate the involvement of HO-1, a heat shock/stress protein, in protection offered by the spin trap agent, N-tert-butyl-alpha-phenyl-nitrone (PBN), against kidney ischemia/reperfusion injury. For this, HO-1 expression and assessment of the parameters associated with tissue-oxidative injury were compared in the presence or absence of PBN pretreatment of rats (100 mg/kg i.p., 30 min) before the onset of 30-min ischemia. Twenty-four hours after reperfusion, Northern blot analysis showed an unprecedented approximately 37-fold increase in 1.8-kb HO-1 mRNA in PBN pretreated rat kidney; HO-2 mRNA levels did not increase. At 48 h, the levels of HO-1 mRNA remained nearly 14-fold higher than the control value. In the absence of PBN, the levels measured approximately 5- and 2-fold higher than control values at the 24- and 48-h intervals, respectively. PBN pretreatment also resulted in a most impressive increase in the levels of HO-1 protein as judged by Western blot analysis and measurement of enzyme activity at the 24-h time point. As detected by immunohistochemical analysis, PBN pretreatment caused an increase in HO-1 and biliverdin reductase-immunoreactive proteins in the cortex and in the outer stripe of the outer medulla. In the absence of PBN pretreatment, there was an intense immunostaining for HO-1 in the medullary rays, which corresponded with iron and lipid peroxidation staining of the region; these observations were not made with PBN-pretreated kidneys. Collectively, the findings are consistent with the likelihood that suprainduction of HO-1 gene expression protects the kidney from free radical-mediated injury by increasing the capacity to produce the potent cellular antioxidant bilirubin. We also suggest spin trap-mediated protection against ischemia/reperfusion injury is likely due to a sustained elevation of HO-1 gene expression by formation of stable radicals.
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PMID:Spin trap (N-t-butyl-alpha-phenylnitrone)-mediated suprainduction of heme oxygenase-1 in kidney ischemia/reperfusion model: role of the oxygenase in protection against oxidative injury. 1052 16

We examined the effects of upregulation of heme oxygenase-1 (HO-1) in steatotic rat liver models of ex vivo cold ischemia/reperfusion (I/R) injury. In the model of ischemia/isolated perfusion, treatment of genetically obese Zucker rats with the HO-1 inducer cobalt protoporphyrin (CoPP) or with adenoviral HO-1 (Ad-HO-1) significantly improved portal venous blood flow, increased bile production, and decreased hepatocyte injury. Unlike in untreated rats or those pretreated with the HO-1 inhibitor zinc protoporphyrin (ZnPP), upregulation of HO-1 by Western blots correlated with amelioration of histologic features of I/R injury. Adjunctive infusion of ZnPP abrogated the beneficial effects of Ad-HO-1 gene transfer, documenting the direct involvement of HO-1 in protection against I/R injury. Following cold ischemia/isotransplantation, HO-1 overexpression extended animal survival from 40% in untreated controls to about 80% after CoPP or Ad-HO-1 therapy. This effect correlated with preserved hepatic architecture, improved liver function, and depressed infiltration by T cells and macrophages. Hence, CoPP- or gene therapy-induced HO-1 prevented I/R injury in steatotic rat livers. These findings provide the rationale for refined new treatments that should increase the supply of usable donor livers and ultimately improve the overall success of liver transplantation.
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PMID:Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury. 1058 8

Heme oxygenase (HO) is believed to be a potent antioxidant enzyme in the nervous system; it degrades heme from heme-containing proteins, giving rise to carbon monoxide, iron, and biliverdin, which is rapidly reduced to bilirubin. The first identified isoform of the enzyme, HO1, is an inducible heat-shock protein expressed in high levels in peripheral organs and barely detectable under normal conditions in the brain, whereas HO2 is constitutive and most highly concentrated in the brain. Interestingly, although HO2 is constitutively expressed, its activity can be modulated by phosphorylation. We demonstrated that bilirubin, formed from HO2, is neuroprotectant, as neurotoxicity is augmented in neuronal cultures from mice with targeted deletion of HO2 (HO2(-/-)) and reversed by low concentrations of bilirubin. We now show that neural damage following middle cerebral artery occlusion (MCAO) and reperfusion, a model of focal ischemia of vascular stroke, is substantially worsened in HO2(-/-) animals. By contrast, stroke damage is not significantly altered in HO1(-/-) mice, despite their greater debility. Neural damage following intracranial injections of N-methyl-d-aspartate (NMDA) is also accentuated in HO2(-/-) animals. These findings establish HO2 as an endogenous neuroprotective system in the brain whose pharmacologic manipulation may have therapeutic relevance.
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PMID:Heme oxygenase-2 is neuroprotective in cerebral ischemia. 1060 74

Sublethal hyperthermia and the following recovery from this heat exposure, referred to as hyperthermic preconditioning, elicits a transient state of tolerance to oxidative insults through an intracellular protective response: stress response. The impact of hyperthermic preconditioning on hepatic microcirculatory disturbance, which is one of the determinants of ischemia/reperfusion-induced injury of the liver, was investigated by using intravital fluorescence microscopy. Thirty minutes of ischemia and a subsequent 120 minutes of reperfusion was induced in an in situ isolated perfusion model of Sprague-Dawley rats. Heat stress was given by whole-body hyperthermia, and a subsequent recovery was allowed for 18 or 48 hours, respectively. Postischemic decrease in sinusoidal perfusion rate and sinusoidal diameter, leukocyte stagnation in sinusoids, and leukocyte adhesion in postsinusoidal venules were significantly attenuated in both hyperthermia-pretreated groups. A recovery of bile production, a reduction of liver enzyme release, and an attenuation of tissue edema and histological damage were also observed. A marked expression of heat shock protein (HSP) 70 and heme oxygenase (HO-1)/HSP32 was correlatively observed in the liver tissue coincident with the induction of these protective effects. Hyperthermic preconditioning provides a continuous long-term and constant inhibitory effect (up to 48 hours after heat exposure) on postischemic injury of the liver through the attenuation of microcirculatory disturbances. These beneficial effects might be associated with a concomitant increase in HSP70 and HO-1/HSP32 expression.
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PMID:Impact of hyperthermic preconditioning on postischemic hepatic microcirculatory disturbances in an isolated perfusion model of the rat liver. 1065 64

Doxorubicin produces clinically useful responses in a variety of human cancers. However, the toxicity of doxorubicin has limited its usefulness. This side effect is mainly due to the doxorubicin-mediated free radical formation. Administration of doxorubicin (10 mg/kg body weight) to rats intravenously induces heme oxygenase-1 (HO-1) in the liver. The levels of HO-1 protein were first detected at 6 hours and peaked at about 18 to 24 hours after the injection. It is known that HO-1 plays a protective role against the oxidative injury. Therefore, we have examined the protective effect of doxorubicin preconditioning against the hepatic ischemia-reperfusion injury. Partial hepatic ischemia was produced in the left and medium lobes for 45 minutes followed by 120 minutes reperfusion. When low doses of doxorubicin (1 mg/kg body weight) was intravenously administered to rats 2 days before the ischemia, the serum alanine transaminase (ALT) levels in the preconditioning rat were clearly improved compared with those in the rat without preconditioning. Under this situation, zinc-protoporphyrin IX, a specific inhibitor of HO-1, was injected subcutaneously to rats at 3 and 16 hours before the ischemia, the ALT levels were not improved by doxorubicin preconditioning. Histopathologic examination also supported these results. Although the HO-1 protein level was fairly low 2 days after the doxorubicin administration, significant amounts of HO-1 protein were detected. Our results indicated that the induction of HO-1 played a protective role against hepatic ischemia-reperfusion injury and that doxorubicin preconditioning is more clinically useful than other preconditioning methods.
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PMID:Doxorubicin preconditioning: a protection against rat hepatic ischemia-reperfusion injury. 1065 83

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