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-oxygenases (HOs) catalyze the conversion of heme into carbon monoxide and biliverdin. HO-1 is induced during hypoxia, ischemia/reperfusion, and inflammation, providing cytoprotection and inhibiting leukocyte migration to inflammatory sites. Although in vitro studies have suggested an additional role for HO-1 in angiogenesis, the relevance of this in vivo remains unknown. We investigated the involvement of HO-1 in angiogenesis in vitro and in vivo. Vascular endothelial growth factor (VEGF) induced prolonged HO-1 expression and activity in human endothelial cells and HO-1 inhibition abrogated VEGF-driven angiogenesis. Two murine models of angiogenesis were used: (1) angiogenesis initiated by addition of VEGF to Matrigel and (2) a lipopolysaccharide (LPS)-induced model of inflammatory angiogenesis in which angiogenesis is secondary to leukocyte invasion. Pharmacologic inhibition of HO-1 induced marked leukocytic infiltration that enhanced VEGF-induced angiogenesis. However, in the presence of an anti-CD18 monoclonal antibody (mAb) to block leukocyte migration, VEGF-induced angiogenesis was significantly inhibited by HO-1 antagonists. Furthermore, in the LPS-induced model of inflammatory angiogenesis, induction of HO-1 with cobalt protoporphyrin significantly inhibited leukocyte invasion into LPS-conditioned Matrigel and thus prevented the subsequent angiogenesis. We therefore propose that during chronic inflammation HO-1 has 2 roles: first, an anti-inflammatory action inhibiting leukocyte infiltration; and second, promotion of VEGF-driven noninflammatory angiogenesis that facilitates tissue repair.
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PMID:Bifunctional role for VEGF-induced heme oxygenase-1 in vivo: induction of angiogenesis and inhibition of leukocytic infiltration. 1452 60

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). Due to 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 cardiovascular function, and highlight our previous studies 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), atherosclerosis and vascular injury (vein graft stenosis), hypotension (endotoxemia), and ischemia/reperfusion injury (heart). In a chronic renovascular hypertension model, blood pressure elevation, cardiac hypertrophy, acute renal failure, and acute mortality induced by one kidney-one clip surgery are more severe in HO-1 null mice. Moreover, absence of HO-1 leads to accelerated atherosclerotic lesion formation and vein graft disease. In addition, HO-1 null mice with endotoxemia have earlier resolution of hypotension, yet the mortality and the incidence of end organ damage are higher in the absence of HO-1. In contrast, mice with cardiac-specific overexpression of HO-1 have an improvement in cardiac function, smaller myocardial infarcts, 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, while overexpression of HO-1 plays a protective role in ischemia/reperfusion injury.
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PMID:Role of heme oxygenase-1 in cardiovascular function. 1452 47

The extent of graft damage after ischemia-reperfusion reflects the balance between deleterious events and protective factors. Heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) may contribute to cytoprotection by their anti-inflammatory and antiapoptotic properties. For investigating whether HO-1 and VEGF play a role in the adaptive response to ischemia-reperfusion injury after renal transplantation, kidney biopsies were analyzed from living (n = 45) and cadaveric (n = 16) donors, obtained at three time points: at the end of cold storage T(-1), after warm ischemia T(0), and after reperfusion T(+1). The mRNA expression levels of HO-1, VEGF(165), Bcl-2, Bax, and hypoxia inducible factor-1alpha were quantified by real-time reverse transcriptase-PCR, and the HO-1 and VEGF proteins were analyzed by immunohistochemistry. Cadaveric donor kidneys presented higher mRNA expression levels of hypoxia inducible factor-1alpha. In contrast, mRNA expression levels of HO-1, VEGF(165), and Bcl-2 were significantly lower in kidneys from cadaveric donors. Overall, a significant correlation was observed between mRNA expression of Bcl-2 and VEGF(165), between Bcl-2 and HO-1, and between HO-1 and VEGF(165). Moreover, protein expression of HO-1 and VEGF was detected in the same anatomical kidney compartments (glomerulus, arteries, and distal tubules). Renal function at the first week posttransplantation (analyzed by serum creatinine levels) showed a significant correlation with both HO-1 and VEGF mRNA expression, reinforcing the protective role of both genes in the early events of transplantation. It is concluded that the lower expression of HO-1, VEGF(165), and Bcl-2 in cadaveric donor kidneys can reflect a defective adaptation against ischemia-reperfusion injury that may affect their function in the short term.
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PMID:Differential expression of heme oxygenase-1 and vascular endothelial growth factor in cadaveric and living donor kidneys after ischemia-reperfusion. 1463 27

Heme oxygenase-1 (HO-1) is emerging as an important cytoprotective enzyme system in a variety of injury models. To optimize future therapeutic applications of HO-1, it is necessary to delineate the precise functions and mechanisms as well as modes of externally regulating HO-1 expression. Investigations have been limited by difficulties with the generation of HO-1 null mice and the lack of specific HO-1 inhibitors. Lung ischemia-reperfusion (I-R) injury is the inciting event in acute lung failure following transplantation, surgery, and shock. To study the function of HO-1 in I-R-induced lung injury, we designed small interfering RNA (siRNA) sequences that effectively suppress HO-1 expression both in vitro and in vivo in an organ-specific manner. In this study we show that there is enhanced apoptosis, via increased Fas expression and caspase 3 activity, in the presence of HO-1 siRNA in endothelial cells and mouse lung during I-R injury, whereas HO-1 overexpression attenuates apoptosis. To the best of our knowledge, we are the first to demonstrate that lung-specific siRNA delivery can be achieved by intranasal administration without the need for viral vectors or transfection agents in vivo, thereby obviating potential concerns for toxicity if siRNA technology is to have clinical application in the future.
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PMID:Small interfering RNA targeting heme oxygenase-1 enhances ischemia-reperfusion-induced lung apoptosis. 1468 67

Heme oxygenase-1 (HO-1) is a member of the heat shock protein family (HSP-32). It responds to thermal stress in cultured glial cells. To our knowledge. nothing is known about the expression and response of the HO-1 in cerebral ischemia. Therefore, we show here the induction of HO-1 in the brain of mice after global cerebral ischemia. HO-1-like immunoreactivity was detected at 12, 24, and 48 hours after ischemia recirculation. The HO-1-like immunoreactive cells were observed in astrocytes in the hippocampal dentate gyrus and CA1. The peak level of HO-1-like immunoreactivity was found 48 hours after the recirculation. HO-1-like immunoreactivity was observed in GFAP-positive astrocytes by use of a double immunostaining method. These results provide direct evidence for the induction and localization of HO-1 immunoreactivity in vivo in a mouse cerebral ischemia. We suggest that HO-1, produced in astrocytes after ischemia-recirculation, may directly affect neurons to protect from cell death.
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PMID:Hippocampal heme oxigenase-1 in a murine cardiac arrest model. 1475 15

INTRODUCTION: Heme oxygenase-1 (HO-1) is a stress response enzyme, which catalyses the breakdown of heme into biliverdin-IX alpha, carbon monoxide and ferrous iron. Under situations of oxidative stress, heat stress, ischemia/reperfusion injury or endotoxemia, HO-1 has been shown to be induced and to elicit a protective effect. The mechanism of how this protective effect is executed is unknown. RESULTS: HO-1 induction with cobalt protoporphorin (Co-PP) dose-dependently protected against apoptotic cell death as well as neutrophil-mediated oncosis in the galactosamine/endotoxin (Gal/ET) shock model. Induction of HO-1 with Co-PP dose-dependently protected against neutrophil-mediated oncosis as indicated by attenuated ALT release and TNF-mediated apoptotic cell death as indicated by reduced caspase-3 activation. HO-1 induction did not attenuate Gal/ET-induced TNF-alpha formation. Furthermore, a similar protective effect with the high dose of Co-PP was observed when animals were treated with Gal/TNF-alpha. CONCLUSIONS: HO-1 induction attenuates apoptosis and neutrophil-mediated oncosis in the Gal/ET shock model. However, the protective effect is not due to the reduction of TNF-alpha release or the attenuation of neutrophil accumulation in the liver sinusoids.
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PMID:Heme oxygenase-1 induction in hepatocytes and non-parenchymal cells protects against liver injury during endotoxemia. 1496 Jan 94

Heme oxygenase-1 (HO-1) degrades heme into iron, biliverdin, and carbon monoxide (CO). HO-1 expression can be used therapeutically to ameliorate undesirable consequences of ischemia reperfusion injury (IRI), but the mechanism by which this occurs, remains to be established. Rat hearts, exposed to a prolonged period (24 h) of cold (4 degrees C) ischemia, failed to function upon transplantation into syngeneic recipients. Induction of HO-1 expression by administration of cobalt protoporphyrin IX (CoPPIX) to the graft donor restored graft function. Inhibition of HO-1 enzymatic activity, by administration of zinc protoporphyrin (ZnPPIX) at the time of transplantation, reversed the protective effect of HO-1. Exposure of the graft donor as well as the graft (during ischemia) to exogenous CO mimicked the protective effect of HO-1. This was associated with a significant reduction in the number of cells undergoing apoptosis in the graft with no apparent decrease of intravascular fibrin polymerization, platelet aggregation, or P-selectin expression. In conclusion, HO-1-derived CO prevents IRI associated with cardiac transplantation based on its antiapoptotic action. The observation that exposure of the donor and the graft to CO is sufficient to afford this protective effect should have important clinical implications in terms of preventing IRI associated with heart transplantation in humans.
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PMID:Heme oxygenase-1-derived carbon monoxide protects hearts from transplant associated ischemia reperfusion injury. 1497 80

Heme oxygenase (HO) modulates the accumulation of leukocytes within the liver during the early stages of a systemic inflammatory response syndrome (SIRS), but the anti-inflammatory mechanism(s) remain to be tested. The influence of HO on the adhesion molecule expression within the liver and on circulating leukocytes was assessed. In addition, the effect of HO and nitric oxide synthase (NOS) on the liver microcirculation was tested. Mice were subjected to 1 h bilateral hindlimb ischemia followed by 3 h of reperfusion, at which time blood samples and the liver were harvested and adhesion molecule expression determined (ICAM-1, CD49d and CD11b). Direct measures of sinusoidal diameter and estimates of volumetric blood flow were obtained using intravital microscopy. HO was specifically induced and inhibited by hemin and chromium mesoporphyrin (CrMP), respectively, whereas NOS was inhibited by N-nitro-L-arginine methyl ester (L-NAME). ICAM-1 expression was increased following hindlimb ischemia-reperfusion. Hemin caused only a modest, but significant decrease in ICAM-1 expression, whereas inhibition of HO had no effect. However, HO inhibition significantly reduced sinusoidal diameters and volumetric flow and such vessels were correlated with significantly increased numbers of stationary leukocytes. Inhibition of NOS had no effect on sinusoidal diameter or volumetric flow. In conclusion, the anti-inflammatory benefits afforded by HO activity within the liver appear to involve the control of sinusoidal diameter and volumetric blood flow rather than altered adhesion molecule expression during the early stages of SIRS.
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PMID:Heme oxygenase modulates hepatic leukocyte sequestration via changes in sinusoidal tone in systemic inflammation in mice. 1521 17

Heme oxygenase (HO), the enzyme responsible for heme catabolism, has been associated with the function of both skeletal and smooth muscle cells and with protection of the heart against ischemia/reperfusion injury. Exposure of skeletal muscle cultures to heme, the physiological substrate for HO, has been shown to improve differentiation and aerobic metabolism. Little is known, however, about the roles that heme and heme metabolism play in cardiac muscle, and the present study was conducted to examine the effects of exogenous heme on cultured heart cells in the presence or absence of modulators of HO activity. Treatment of neonatal rat ventricular cells with heme resulted in increases in four key indicators: (1) the activity of metabolic enzymes, (2) the rate of spontaneous contraction, (3) the level of myosin heavy chain (MyHC) expressed, and (4) the amount of actin organized as filaments. Treatment with heme while metabolically inhibiting increased HO activity altered these effects such that: (1) increases in enzyme activities were attenuated, (2) spontaneous beating ceased, (3) the level of MyHC was reduced, and (4) the amount of filamentous actin was severely decreased to the point where myofibrils were no longer evident. These results suggest that heme and its catabolites act to modulate aspects of cardiac cell function and organization.
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PMID:Exogenous metalloporphyrins alter the organization and function of cultured neonatal rat heart cells via modulation of heme oxygenase activity. 1528 Oct 86

Heme oxygenase-1 (HO-1) is induced as an adaptive and protective response to tissue injury. HO-1 degrades heme into carbon monoxide (CO) and biliverdin; the latter is then converted to bilirubin. These reaction products have powerful antiapoptotic and antioxidant effects. Manipulation of the HO-1 system by administration of micromolar doses of exogenous CO or bilirubin has been performed in several organ systems, but the dose-related effects of these reaction products have not been investigated in the kidney. The purpose of this study was to evaluate the efficacy and dose-related protective effects of 1 or 10 muM bilirubin flush before a 20-min period of warm ischemia. In an effort to minimize interactions with other chemical messengers or organ systems, we elected to use an isolated, perfused rat kidney model with an acellular, oxygenated perfusate. Using this model, we demonstrated that bilirubin treatment resulted in significant improvements in renal vascular resistance, urine output, glomerular filtration rate, tubular function, and mitochondrial integrity after ischemia-reperfusion injury (IRI). Beneficial effects on organ viability were achieved most consistently with a dose of 10 muM bilirubin. We conclude that the protective effects of HO-1 activity during IRI in the kidney are mediated, at least in part, by bilirubin and that pretreatment with micromolar doses of bilirubin may offer a simple and inexpensive method to improve renal function after IRI.
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PMID:Protective effects of exogenous bilirubin on ischemia-reperfusion injury in the isolated, perfused rat kidney. 1556 77


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