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-1) is a stress protein that has been suggested to participate in defense mechanisms against agents that induce oxidative injury such as hemoglobin/heme, hypoxia-ischemia and cytokines. Overexpression of HO-1 in endothelial cells (EC) might, therefore, protect against oxidative stress produced under these pathological conditions, by generation of CO, a vasodilator, and bilirubin, which has antioxidant properties that enhance blood vessel formation to counteract hypoxia-induced injury. A plasmid containing the cytomegalovirus promoter (pCMV) neomycin human HO-1 gene complexed to cationic liposomes, lipofectin, was used to transfect rabbit coronary microvessel EC. Cells transfected with human HO-1 gene demonstrated a twofold increase in HO activity and maintained a similar phenotype as in the nontransfected cells. Cell number in transfected cells with human HO-1 gene increased by about 45%, as compared to nontransfected or those transfected with control pCMV. Transfected and nontransfected EC revealed a similar response to basic fibroblast growth factor (bFGF) in capillary formation. However, transfected cells with the human HO-1 gene exhibited a twofold increase in blood vessel formation. The angiogenic response of EC to overexpression of HO-1 gene provides direct evidence that the inductive form of HO-1 following injury represents an important tissue adaptive mechanism for moderating the severity of cell damage produced in inflammatory reaction sites of hemorrhage, thrombosis and hypoxic-ischemia. Thus, HO-1 may participate in the regulation of EC activation, proliferation and angiogenesis.
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PMID:Gene transfer of human heme oxygenase into coronary endothelial cells potentially promotes angiogenesis. 940 20

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

Cells respond to external stimuli by changes in gene expression that are largely dependent on transcription factors (TFs). We studied the behavior of some TFs in rat liver during ischemia, postischemic reperfusion, and heat shock. Knowledge of the conditions at the end of ischemia is essential to understand changes occurring at reperfusion. The TFs investigated are known to be typically responsive to heat shock (HSF), hypoxia (HIF-1), pro- and antioxidant conditions (AP-1), or to various environmental changes (HNF-1 and ATF/CREB family). The most relevant new information includes the following: 1) Liver ischemia activates extremely rapidly the DNA binding capacity of HSF, soon followed by analogous activation of HIF-1 and AP-1. 2) After a certain lag time from the activation of HIF-1, mRNAs accumulate for two glycolytic enzymes, in particular Aldolase A and Heme Oxygenase 1, which contain HIF-1 sequences in their promoters. 3) Reperfusion, which is known to further increase the binding of HSF and to induce NFkappaB binding, abrogates or decreases the binding of HIF-1 and AP-1, stimulated by ischemia, and activates the binding of ATF/CREB. Later on, a second peak of AP-1 binding is induced. 4) Heat shock activates both ischemia-responsive and reperfusion-responsive TFs. 5) Preliminary experiments of supergelshift reveal that the activation of AP-1 at reperfusion or upon heat shock may result from the different involvement of the component subunits.
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PMID:Differential activation of some transcription factors during rat liver ischemia, reperfusion, and heat shock. 1039 95

Accumulating evidence on the molecular and cellular basis of ischemia/reperfusion-induced neurodegeneration suggests that oxidative stress is involved. Heme oxygenase (HO) and cyclooxygenase (COX) play physiologically important roles in the CNS. Conversely, HO and COX also can increase oxidative stress. Recent studies suggest that c-Jun phosphorylation is an important step in some forms of stress-induced neuronal apoptosis. In this study, the authors tried to clarify the association of HO and COX with c-Jun phosphorylation. Inducible forms of HO and COX (HO-1 and COX-2, respectively) were transiently induced in CA1 pyramidal neurons after ischemia. c-Jun also was induced in pyramidal neurons throughout the hippocampal formation, but its phosphorylation was limited to CA1. In contrast, these molecules were constitutively expressed at low levels. Most (84%) of the CA1 pyramidal neurons examined expressed HO-1, COX-2, or both, and such expression showed good co-localization with c-Jun phosphorylation. These results suggest the following: (1) c-Jun phosphorylation was associated with ischemia/reperfusion-induced neuronal apoptosis; (2) HO-1 and COX-2 were induced in CA1 pyramidal neurons, which undergo cell death; and (3) most CA1 pyramidal neurons expressed HO-1, COX-2, or both, which strongly suggests that these are candidates for neuron killers.
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PMID:Phosphorylation of c-Jun and its localization with heme oxygenase-1 and cyclooxygenase-2 in CA1 pyramidal neurons after transient forebrain ischemia. 1056 71

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

Sudden infant death syndrome (SIDS) occurs silently usually during sleep and, though remaining unexplained after autopsy, leaves footprints creating a pattern analogous to that which follows a flood of nitric acid (NO). These footprints in SIDS are associated with serious pathological changes, viz. elevated hepatic iron, bone marrow hyperplasia, hypomyelinated respiratory control centres, elevated lung immunoglobulins, cerebral hypoperfusion resembling lesions induced by chronic hypoxemia, ischemia, congenital heart disease and congenital myopathy. Hypoxia stimulates the immune response and the over-arousal of the immune response triggers a flood of NO. Adenosine triggers sleep. NO and adenosine are additive as dilators of coronary blood vessels. Blood pressure collapses. Selenium increases the activity of the enzyme ferrochelatase during incorporation of heme into cytochrome oxidase. NO binds to cytochrome oxidase, inhibiting respiration. When NO reaches dangerous levels, the cell turns on production of heme oxygenase. Heme is broken down to iron (Fe) carbon monoxide (CO) and bile pigments. NO has a huge affinity for hemoglobin which catalyses NO degradation to nitrate. Furthermore, NO is a product of smoke and SIDS incidence is higher in smoking mothers.
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PMID:Association of sudden infant death syndrome with grossly deranged iron metabolism and nitric oxide overload. 1079 Jul 39

Heme oxygenase-1, an inducible heat shock protein, is upregulated by oxidative stress, and its expression is modulated by proinflammatory cytokines such as IL-1 and IL-6. In the present study, we investigated the effects of postlesional, orally applied ebselen, a neuroprotective antioxidant, on serum levels of IL-6 and cerebral heme oxygenase-1 expression following focal ischemia induced by photothrombosis. Ebselen (50 mg/kg body weight) was given 30 min postlesion to male Wistar rats. Animals were divided into four groups: sham-operated vehicle control (n = 9), sham-operated ebselen control (n = 8), lesioned vehicle control (n = 14), and lesioned ebselen-treated (n = 17). Ebselen treatment resulted in a significant lowering of IL-6 plasma levels (26 +/- 5 pg/ml) as compared with that seen in lesioned vehicle controls (48 +/- 9 pg/ml) at 24 h postlesion. In sham-operated rats IL-6 was not detectable. Heme oxygenase-1-positive glial cells were quantitated within topographically determined perilesional brain regions. Within the 0.5-mm-wide rim region directly associated with the lesion core, no differences in the amount of heme oxygenase-1-positive glial cells were found. However, in the more remote ipsilateral perilesional cortex, significantly fewer heme oxygenase-1-positive glial cells were present within the supragranular cortical layers of lesioned ebselen-treated rats compared to lesioned vehicle controls (P < 0.001). In sham-operated rats, no glial heme oxygenase-1 induction occurred. The results indicate that postlesional ebselen treatment lowered plasma IL-6 levels subsequent to a photothrombotic lesion concomitant with a lowering of the heme oxygenase-1 response in glial cells.
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PMID:Ebselen lowers plasma interleukin-6 levels and glial heme oxygenase-1 expression after focal photothrombotic brain ischemia. 1093 77

Heme oxygenase (HO) cleaves the heme ring to form biliverdin, which is rapidly reduced to bilirubin, carbon monoxide, and iron. HO1, the first form of the enzyme discovered, is an inducible protein, concentrated in tissues that are exposed to degrading red blood cells and stimulated by hemolysis and numerous other toxic perturbations to eliminate potentially toxic heme. By contrast, HO2 is constitutive and most highly concentrated in neural tissues. Carbon monoxide, formed from HO2, is a putative neurotransmitter in the brain and peripheral autonomic nervous system. HO1 regulates the efflux of potentially toxic iron from cells, as iron efflux is deficient in mice with targeted deletion of HO1 (HO1(-/-)), and transfection of HO1 facilitates iron efflux. Bilirubin appears to be a physiologic neuroprotectant. Activation of HO2 by phorbol esters, that stimulate protein kinase C to phosphorylate HO2, augments production of bilirubin which protects brain cultures from oxidative stress. Bilirubin itself in nanomolar concentrations is neuroprotective, while HO2 deletion (HO2(-/-)) leads to increased neurotoxicity in brain cultures and increased neural damage following transient cerebral ischemia in intact mice. Mechanisms whereby HO2 provides neuroprotection have not been clarified including whether protection is primarily associated with apoptotic or necrotic cell death. Moreover, the generality of neurotoxic stimuli influenced by HO2 has been unclear. We now demonstrate increased neuronal death in cerebellar granule cultures of HO2(-/-) mice with a selective augmentation of apoptotic death. We also demonstrate that HO2 transfection rescues apoptotic death. In intact mice, we show an increased incidence of apoptotic morphology in the penumbra area surrounding the infarct core in HO2(-/-) mice undergoing transient focal ischemia.
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PMID:Heme oxygenase-2 acts to prevent neuronal death in brain cultures and following transient cerebral ischemia. 1097 22

Enhanced production of reactive oxygen species plays a role in myocardial injury following ischemia/reperfusion. Heme oxygenase-1 (HO-1) is a heme-catabolizing enzyme that is induced by and acts against oxidant-induced tissue injury. We examined whether HO-1 expression was regulated following ischemia and reperfusion in the rat heart. HO-1 expression increased as early as 24 h after reperfusion. Strong HO-1 expression was seen in monocytes/macrophages and myofibroblasts. Next, we examined whether the induction of HO-1 could ameliorate cardiac injury following ischemia/reperfusion. Intraperitoneal hemin injection (30 mg/kg/day) for 2 days prior to the operation resulted in an about 2.8-fold increase in HO-1 expression in the rat heart. Hemin treatment significantly decreased infarct area (6 +/- 2%) compared to the control (21 +/- 2%), which was reversed by the coadministration of an HO inhibitor in a dose-dependent manner. Our data suggest that induction of HO-1 can reduce the cardiac injury in vivo following ischemia/reperfusion.
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PMID:Induction of heme oxygenase-1 can act protectively against cardiac ischemia/reperfusion in vivo. 1111 29

Heme-hemopexin (2-10 microM) is used as a model for intravenous heme released in trauma, stroke, and ischemia-reperfusion. A transient increase in cellular protein oxidation occurs during receptor-mediated heme transport from hemopexin which is inhibited by the nonpermeable Cu(I) chelator, bathocuproinedisulfonate. Thus, participation of surface redox process involving Cu(I) generation are proposed to be linked to the induction of the protective proteins heme oxygenase-1 (HO-1) and metallothionein-1 (MT-1) by heme-hemopexin. The region (-153 to -42) in the proximal promoter of the mouse MT-1 gene responds to heme- and CoPP-hemopexin in transient transfection assays and contains metal-responsive elements for MTF-1 and an antioxidant-responsive element (ARE) overlapping a GC-rich E-box to which USF-1 and -2 bind. No decreases in DNA binding of the diamide-oxidation sensitive USF-1 and -2 occur upon exposure of cells to heme-hemopexin. MTF-1 and the ARE-binding proteins are relatively resistant to diamide oxidation and are induced approximately eight- and two-fold, respectively, by heme-hemopexin. BCDS prevents the nuclear translocation of MTF-1 by both heme- and CoPP-hemopexin complexes as well as MT-1 mRNA induction by CoPP-hemopexin. Thus, copper is needed for the surface oxidation events and yet the nuclear translocation of MTF-1 in response to hemopexin occurs via copper, probably Cu(I),-dependent signaling cascades from the hemopexin receptor rather than the oxidation per se.
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PMID:Role for copper in transient oxidation and nuclear translocation of MTF-1, but not of NF-kappa B, by the heme-hemopexin transport system. 1121 79


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