Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carvedilol, a new vasodilating beta-adrenoceptor antagonist and a potent antioxidant, produces a high degree of cardioprotection in a variety of experimental models of ischemic cardiac injury. Recent clinical studies in patients with heart failure have demonstrated that carvedilol reduces morbidity and mortality and inhibits cardiac remodeling. The present study was designed to explore whether the protective effects of carvedilol on the ischemic myocardium include inhibition of apoptosis of cardiomyocytes and, if so, to determine its mechanism of action. Anesthetized rabbits were subjected to 30 minutes of coronary artery occlusion followed by 4 hours of reperfusion. Detection of apoptosis of cardiomyocytes was based on the presence of nucleosomal DNA fragments on agarose gels (DNA ladder) and in situ nick end labeling. Carvedilol (1 mg/kg IV), administered 5 minutes before reperfusion, reduced the number of apoptotic myocytes in the ischemic area from 14.7 +/- 0.4% to 3.4 +/- 1.8% (77% reduction, P<.001). Propranolol, administered at equipotent beta-blocking dosage, reduced the number of apoptotic myocytes to 8.9 +/- 2.1% (39% reduction, P<.05). DNA ladders were observed in the hearts of all six vehicle-treated rabbits but only one of six carvedilol-treated rabbits (P<.01). Immunocytochemical analysis of rabbit hearts demonstrated an upregulation of Fas protein in ischemic cardiomyocytes, and treatment with carvedilol reduced both the intensity of staining as well as the area stained. Myocardial ischemia/reperfusion led to a rapid activation of stress-activated protein kinase (SAPK) in the ischemic area but not in nonischemic regions. SAPK activity was increased from 2.1 +/- 0.3 mU/mg (basal) to 8.9 +/- 0.8 mU/mg after 30 minutes of ischemia followed by 20 minutes of reperfusion. Carvedilol inhibited the activation of SAPK by 53.4 +/- 6.5% (P<.05). Under the same conditions, propranolol (1 mg/kg) had no effect on SAPK activation. Taken together, these results suggest that carvedilol prevents myocardial ischemia/reperfusion-induced apoptosis in cardiomyocytes possibly by downregulation of the SAPK signaling pathway, by inhibition of Fas receptor expression, and by beta-adrenergic blockade. The former two actions represent novel and important mechanisms that may contribute to the cardioprotective effects of carvedilol.
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PMID:Possible involvement of stress-activated protein kinase signaling pathway and Fas receptor expression in prevention of ischemia/reperfusion-induced cardiomyocyte apoptosis by carvedilol. 946 87

Several cardioprotective proteins are induced during myocardial ischemia, such as heat shock proteins and anti-apoptotic Bcl-2-related proteins which, when experimentally overexpressed, have been shown to prevent ischemia-induced myocyte loss. As this pathophysiological induction is obviously not sufficient to prevent losses of myocytes, we analysed whether it could occur under moderate myocardial ischemia with hibernation, thus potentially contributing to myocyte protection under these conditions. Therefore, using anesthetized pigs with documented myocardial hypoperfusion and short-term hibernation, we investigated the left ventricular mRNA expression of the inducible heat shock protein Hsp70 and of the anti-apoptotic Bcl-XL in comparison with the pro-apoptotic Bak and Fas expression. For transcriptional analyses, the porcine cDNA sequences of Bcl-XL, Bak and Fas were identified by polymerase chain reaction (PCR) or by screening of a porcine heart cDNA library and cloned. Using reverse transcription polymerase chain reaction (RT-PCR), we observed an unchanged mRNA expression of inducible Hsp70, Bcl-XL, Bak and Fas after 85 min of hypoperfusion in the short-term hibernating myocardium, as well as after 30 min of subsequent reperfusion in the stunned myocardium, compared with transcription in a non-hypoperfused control area of the same ventricle. In conclusion, the mRNA expression of inducible Hsp70 and of several apoptosis-modulating proteins is not altered during moderate myocardial ischemia resulting in short-term hibernation of the affected area and during subsequent stunning.
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PMID:Quantification of cardioprotective gene expression in porcine short-term hibernating myocardium. 1007 23

The outcome of myocardial ischemia-reperfusion has been partially attributed to the degree of apoptosis in cardiomyocytes. Aggregating platelets by release of transforming growth factor-beta(1) (TGF-beta(1)) protect the isolated heart against ischemia-reperfusion injury and preserve myocardial TGF-beta(1) content. To gain more insight into the modulation of hypoxia-reoxygenation-induced injury (apoptosis and necrosis) to myocytes by TGF-beta(1) and aggregating platelets, cultured adult rat myocytes were exposed for 48 or 72 h to hypoxia alone, or to hypoxia followed by 3 h of reoxygenation. Apoptosis in the cells was determined by in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining and DNA fragmentation on gel electrophoresis. Hypoxia alone caused a time-dependent increase in myocyte apoptosis (number of apoptotic cells: 19+/-3% at 48 h and 39+/-5% at 72 h compared with 5+/-1% in control cells, based on a 500-cell count). Three hours of reoxygenation after 48 h of hypoxia further increased the number of apoptotic cells (34+/-8 versus 19+/-3% in hypoxia for 48 h), but reoxygenation after 72 h of hypoxia did not additionally increase the number of apoptotic cells, perhaps because of extensive cell necrosis on prolonged hypoxia. Forty-eight hours of hypoxia followed by 3 h of reoxygenation also resulted in a decrease in Bcl-2 and an increase in Fas protein level. Incubation of myocytes with either recombinant TGF-beta(1) (0.5-5 ng/ml) or aggregated platelet supernatant (from 2-3 x10(7) platelets/ml, containing approximately 0.5 ng/ml of TGF-beta(1)) markedly (P<.01) decreased the number of apoptotic cells after hypoxia-reoxygenation. Incubation with TGF-beta(1) also reduced myocyte necrosis as evident from lactate dehydrogenase release and trypan blue dye exclusion. These data demonstrate that hypoxia-reoxygenation results in apoptosis and necrosis in cultured adult rat myocytes; this can be attenuated by TGF-beta(1). Similarity of data with TGF-beta(1) and aggregated platelet supernatant suggests that platelet-mediated cardioprotection during hypoxia-reoxygenation may relate in part to the release of TGF-beta(1).
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PMID:Hypoxia-reoxygenation-induced apoptosis in cultured adult rat myocytes and the protective effect of platelets and transforming growth factor-beta(1). 1052 94

Serum levels of soluble Fas, soluble Fas ligand, and nuclear matrix protein (NMP) were measured in 38 patients with ischemic heart disease before and after coronary angiography or coronary intervention. Serum levels of soluble Fas, soluble Fas ligand and NMP were determined by enzyme-linked immunosorbent assay. Patients one week after undergoing stent implantation had much higher levels of soluble Fas ligand and significantly lower levels of soluble Fas than patients without coronary intervention. Serum levels of soluble Fas ligand and NMP in patients with coronary restenosis were significantly higher than those in patients without restenosis. Serum levels of soluble Fas and soluble Fas ligand in patients one week after undergoing stent implantation who had coronary restenosis were markedly lower and higher than in patients without restenosis, respectively. Serum levels of soluble Fas ligand were positively correlated with NMP in those patients. These results indicate that coronary restenosis might be affected by the Fas/Fas ligand system. We conclude that measurement of soluble Fas, soluble Fas ligand and NMP is useful for determination of coronary restenosis in patients with ischemic heart disease.
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PMID:[Evaluation of restenosis by serum levels of soluble Fas, Fas ligand and nuclear matrix protein before and after coronary intervention]. 1071 29

Fas ligand (FasL) induces apoptotic cell death when bound to Fas antigen. The engagement of FasL has anti-inflammatory effects through the prevention of cell proliferation and cytokine secretion. However, the role of FasL in myocardial ischemia/reperfusion (MI/R) injury is unclear. We examined the expression of FasL mRNA in the myocardium of MI/R rats by ligating the left coronary artery for 30 minutes and allowing reperfusion to occur for 0, 1, 3, and 24 hours. The expression of FasL mRNA was enhanced 1 hour after reperfusion, and enhanced levels were consistently seen after 24 hours of reperfusion. FasL immunostaining was observed on neutrophils, macrophages, T cells, and vascular endothelial cells. We then assessed the potential role of FasL in the cell proliferation and cytokine production seen in MI/R injury after 24 hours of reperfusion. Rats were divided into three groups; Group A, without treatment; Group B, treated with nonspecific rabbit IgG; and Group C, treated with anti-FasL antibody. Anti-FasL antibody or rabbit IgG were administered intravenously before coronary artery occlusion. In Group C, interleukin-1beta and interleukin-2 mRNA levels were decreased, and neutrophil and T cell accumulation was attenuated. The infarct area determined by triphenyltetrazolium chloride staining was significantly smaller in Group C (18 +/- 4%) than in Group A (34 +/- 2%) or Group B (33 +/- 4%) (p< 0.0001). However, there was no significant difference in the prevalence of terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end-labeling-positive cardiomyocytes among the three groups. These findings suggest that the cardioprotective effect of anti-FasL antibody is due to its anti-inflammatory action, rather than antiapoptotic action. The Fas/FasL system may be involved in the development of MI/R injury.
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PMID:Antibody binding to fas ligand attenuates inflammatory cell infiltration and cytokine secretion, leading to reduction of myocardial infarct areas and reperfusion injury. 1221 72

Fas ligand (FasL) is a member of tumor necrosis factor family that induces apoptosis in target cells that express Fas. The function of FasL during inflammation remains controversial. In this study, we examined the role of vascular endothelial FasL during acute myocardial ischemia-reperfusion that is closely associated with inflammation. Transgenic mouse lines were established that overexpress human FasL on endothelium under the control of the vascular endothelial cadherin promoter. Expression of FasL transgene was detected at both mRNA and protein levels, and functional transgene-encoded FasL protein was specifically expressed on the surface of vascular endothelial cells. Transgenic mice developed normally and had normal hearts. When subjected to 30 min of myocardial ischemia and 72 h of reperfusion, myocardial infarct size was reduced by 42% in the transgenic mice compared with nontransgenic littermates (p < 0.05). Moreover, hemodynamic data demonstrated that transgenic hearts performed better following ischemia and reperfusion compared with nontransgenic hearts. Myocardial neutrophil infiltration was reduced by 54% after 6 h of reperfusion in transgenic hearts (p < 0.01). Neutrophil depletion prior to ischemia-reperfusion injury led to smaller infarcts that were not different between transgenic and nontransgenic mice, suggesting that endothelial FasL may attenuate ischemia-reperfusion injury by abating the inflammatory response. These results indicate that vascular endothelial FasL may exert potent anti-inflammatory actions in the setting of myocardial ischemia-reperfusion injury.
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PMID:Endothelial cell overexpression of fas ligand attenuates ischemia-reperfusion injury in the heart. 1257 84

The catalytic activity of calcium-independent phospholipase A2 (iPLA2), which is classified as a group VI PLA2, is regulated by protein kinase C, calmodulin, and others such as reactive oxygen species. Numerous findings have shown that iPLA2 is involved in stimulus-induced arachidonic acid release and lysophospholipid generation, although the participation is dependent upon the cell type and stimulus. The catalytic action of iPLA2 is known to be responsible for phospholipid remodeling as a housekeeping function. However, it has been widely accepted that arachidonic acid and lysophospholipid generated by iPLA2 act as a signaling molecule in cellular functions. Those include eicosanoid production, glucose-induced insulin secretion, Fas-induced apoptosis, cellular proliferation, membrane traffic in fusion, contribution to myocardial ischemia, and others. In this review, the functional role of iPLA2 in cellular responses upon stimulation is the focus.
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PMID:Cellular function of calcium-independent phospholipase A2. 1530 16

We measured serum interleukin-2 receptor (sIL-2R), tumor necrosis factor-a (TNF-a), Fas receptor (sFas), nitric oxide (NO), and angiotensin converting enzyme (ACE) activity in 45 patients with congestive heart failure (CHF) of different etiologies. The relatioship between these bioindices and the severity of heart failure was analysed. Patients were classified according to the etiology of heart failure into: 15 patients with rheumatic valvular heart disease (RHD), 17 with ischemic heart disease (IHD) and 13 with idiopathic dilated cardiomyopathy (DCM). Patients were further classified according to severity of CHF following the New York Heart Association classification (NYHA) into: NYHA class II (n= 7), NYHA class III (n=20) and NYHA class IV (n=18). Eighteen healthy subjects were included as controls. Serum sIL-2R, TNF-alpha and sFas levels were determined by ELISA while serum NO and ACE levels were measured by colorimetric methods. Doppler Echocardiography was performed for all participants. Levels of sIL-2R, TNF-alpha, sFas, NO, and ACE were significantly higher in CHF patients than controls. Levels of the bioindices varied according to the CHF etiology. TNF-a level was the only one that had significant differences among different subgroups (RHD, IHD and DCM). The levels of sIL-2R, TNF-alpha, NO and sFas in patients with NYHA class IV were significantly higher than class II or III. Moreover, sIL-2R, TNF-alpha and NO levels were significantly higher in patients with diastolic dysfunction than patients with normal diastolic function. A significant positive correlations were found between sFas and both TNF-alpha and sIL-2R and between TNF-alpha and both NO and diastolic function. In addition, significant positive correlations were found between TNF-alpha and sIL-2R in both IHD and RHD patients and between sIL-2R and both ACE in IHD patients and diastolic function in DCM patients. It is concluded that a relationship exists between immune system activation, apoptosis and renin- angiotensin system in CHF and this may play a significant role in the pathophysiology and prognosis of the disease.
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PMID:Proinflammatory cytokines, soluble Fas receptor, nitric oxide and angiotensin converting enzyme in congestive heart failure. 1673 38

Recently, we have reported that purified Salvia miltiorrhiza extract (PSME) could prevent myocardial infarction in vivo and myocardial ischemia/reperfusion injury in isolated rat hearts (ex vivo). The aim of this project is to determine whether PSME exerts any cardioprotective effects in vitro. The vascular smooth muscle cell line was used and the effects of the drugs were determined after inducing hypoxia. Gene expression levels of the pro-apoptotic genes Asp53, Bax, and Fas were significantly down-regulated by 0.78-, 0.82-, and 0.87-fold, respectively, and Bcl-2 was up-regulated by 0.82-fold in the PSME-treated groups as compared to the hypoxic group (P<0.05). Significant reduction in immunoreactivity of the protein products of these genes as well as least nuclear green fluorescence observed in TUNEL staining indicate the therapeutic potential of this drug. Furthermore, cardiac antioxidant enzymes assay confirmed this deduction as PSME had slight preserving effects on superoxide dismutase and catalase (0.25 +/- 0.01 vs 0.488 +/- 0.02 units/mg protein and 0.026 +/- 0.012 vs 0.076 +/- 0.01 mumol per min per mg protein, respectively; each P<0.05). No significant results were obtained with glutathione S-transferase and GSH peroxidase antioxidant tests. Our results demonstrated that PSME exerts antioxidant effects in vitro, indicating the therapeutic potential of this drug.
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PMID:Effects of purified Salvia miltiorrhiza extract on cardiac vascular smooth muscle hypoxic cells. 1765 8

During myocardial ischemia, cardiomyocytes can undergo apoptosis or compensatory hypertrophy. Fas expression is upregulated in the myocardial ischemia and is coupled to both apoptosis and hypertrophy of cardiomyocytes. The role of Fas in apoptosis induction or cardiomyocyte hypertrophy during ischemic conditions is, however, still unclear. Some reports suggested that Fas might induce myocardial hypertrophy. Apoptosis of ischemic cardiomyocytes and Fas expression in the nonischemic cardiomyocytes occurs during the early stage of ischemic heart failure. Hypertrophic cardiomyocytes easily undergo apoptosis in response to ischemia, after which apoptotic cardiomyocytes are replaced by fibrous tissue. In the late stage of ischemic heart failure, hypertrophy, apoptosis, and fibrosis are thought to accelerate each other and might thus form a vicious circle that eventually results in heart failure. In this review, we summarize recent advances in the understanding of the role of Fas in remodeling ischemic myocardial tissues.
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PMID:The role of Fas in the progression of ischemic heart failure: prohypertrophy or proapoptosis. 1892 50


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