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)

Myocardial ischemia-reperfusion injury can be related to complement activation with generation of chemotactic agents, adhesion molecule expression, release of cytokines and oxygen-derived free radicals, and subsequent neutrophil accumulation. In the present study the cardioprotective effects of a novel highly selective small molecule C1s inhibitor (C1s-INH-248, Knoll) were examined in a rabbit model of myocardial ischemia (I) and reperfusion (R; i.e., 60 min I + 180 min R). In in vitro tests (enzyme activity and SRBC lysis) C1s-INH-248 demonstrated profound inhibitory potency. In vivo C1s-INH-248 (1 mg/kg body weight) administered 5 min before reperfusion significantly attenuated myocardial injury (31.9 +/- 2.5 vs 8.9 +/- 1.6% necrosis/area at risk; p < 0.01). The cardioprotective effect was dose dependent. The reduction of myocardial injury was also observed as diminished plasma creatine kinase activity in C1s-INH-248-treated animals (70.7 +/- 6.8 vs 45.1 +/- 3.9 U/g protein after 3 h of reperfusion, p < 0.05). Further, cardiac myeloperoxidase activity (i.e., a marker of PMN accumulation) in the ischemic and necrotic area was significantly reduced following C1s-INH-248 treatment (1.31 +/- 0.23 vs 0.4 +/- 0.05 U/100 mg tissue in necrotic area, p < 0.01). Thus, blocking the classical complement pathway with a highly specific and potent synthetic inhibitor of the activated C1 complex appears to be an effective mean to preserve ischemic myocardium from injury following reperfusion.
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PMID:Novel small molecule inhibitor of C1s exerts cardioprotective effects in ischemia-reperfusion injury in rabbits. 1167 55

This study was designed to investigate the effects of various chemically distinct activators of PPAR-gamma and PPAR-alpha in a rat model of acute myocardial infarction. Using Northern blot analysis and RT-PCR in samples of rat heart, we document the expression of the mRNA for PPAR-gamma (isoform 1 but not isoform 2) as well as PPAR-beta and PPAR-alpha in freshly isolated cardiac myocytes and cardiac fibroblasts and in the left and right ventricles of the heart. Using a rat model of regional myocardial ischemia and reperfusion (in vivo), we have discovered that various chemically distinct ligands of PPAR-gamma (including the TZDs rosiglitazone, ciglitazone, and pioglitazone, as well as the cyclopentanone prostaglandins 15D-PGJ2 and PGA1) cause a substantial reduction of myocardial infarct size in the rat. We demonstrate that two distinct ligands of PPAR-alpha (including clofibrate and WY 14643) also cause a substantial reduction of myocardial infarct size in the rat. The most pronounced reduction in infarct size was observed with the endogenous PPAR-gamma ligand, 15-deoxyDelta12,14-prostagalndin J2 (15D-PGJ2). The mechanisms of the cardioprotective effects of 15D-PGJ2 may include 1) activation of PPAR-alpha, 2) activation of PPAR-gamma, 3) expression of HO-1, and 4) inhibition of the activation of NF-kappaB in the ischemic-reperfused heart. Inhibition by 15D-PGJ2 of the activation of NF-kappaB in turn results in a reduction of the 1) expression of inducible nitric oxide synthase and the nitration of proteins by peroxynitrite, 2) formation of the chemokine MCP-1, and 3) expression of the adhesion molecule ICAM-1. We speculate that ligands of PPAR-gamma and PPAR-alpha may be useful in the therapy of conditions associated with ischemia-reperfusion of the heart and other organs. Our findings also imply that TZDs and fibrates may help protect the heart against ischemia-reperfusion injury. This beneficial effect of 15D-PGJ2 was associated with a reduction in the expression of the 1) adhesion molecules ICAM-1 and P-selectin, 2) chemokine macrophage chemotactic protein 1, and 3) inducible isoform of nitric oxide synthase. 15D-PGJ2 reduced the nitration of proteins (immunohistological analysis of nitrotyrosine formation) caused by ischemia-reperfusion, likely due to the generation of peroxynitrite. Not all of the effects of 15D-PGJ2, however, are due to the activation of PPAR-gamma. For instance, exposure of rat cardiac myocytes to 15D-PGJ2, but not to rosiglitazone, results in an up-regulation of the expression of the mRNA for heme-oxygenase-1 (HO-1). Taken together, these results provide convincing evidence that several, chemically distinct ligands of PPAR-gamma reduce the tissue necrosis associated with acute myocardial infarction.
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PMID:Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size. 1208 64

1. Myocardial injury caused by ischaemia and reperfusion comes from multiple pathogenic events, including endothelial damage, neutrophil extravasation into tissue, mast cell activation, and peroxidation of cell membrane lipids. These events are followed by myocardial cell alterations resulting eventually in cell necrosis. An enhanced formation of reactive oxygen species is widely accepted as a stimulus for tissue destruction and cardiac failure. 2. In this study, we have investigated the cardioprotective effects of M40403 in myocardial ischaemia-reperfusion injury. M40403 is a low molecular weight, synthetic manganese containing superoxide dismutase mimetic (SODm) that selectively removes superoxide anion. Ischaemia was induced in rat hearts in vivo by ligating the left anterior descending coronary artery. Thirty minutes after the induction of ischaemia, the ligature was removed and reperfusion allowed to occur for at least 60 min. M40403 (0.1-1 mg kg(-1)) was given intravenously 15 min before ischaemia. 3. The results obtained in this study showed that M40403 significantly reduced the extent of myocardial damage, mast cell degranulation and the incidence of ventricular arrhythmias. Furthermore, M40403 significantly attenuated, in a dose-dependent manner, neutrophil infiltration in the myocardium as well as the associated induction of lipid peroxidation. Calcium overload seen post-reperfusion of the ischaemic myocardium was also reduced by M40403. 4. Immunohistochemical analysis for nitrotyrosine revealed a positive staining in cardiac tissue taken after reperfusion: this was attenuated by M40403. Moreover reperfused cardiac tissue sections showed positive staining for P-selectin and for anti-intercellular adhesion molecule (ICAM-1) in the vascular endothelial cells. M40403 treatment markedly reduced the intensity and degree of P-selectin and ICAM-1 in these tissues. No staining for nitrotyrosine, P-selectin or ICAM-1 was found in cardiac tissue taken at the end of the ischaemic period. 5. Overall, M40403 treatment reduced the morphological signs of myocardial cell injury and significantly improved survival. 6. Taken together, these results clearly indicate that M40403 treatment exerts a protective effect against ischaemia-reperfusion-induced myocardial injury, supporting a key role for superoxide anion in reperfusion injuries. This suggests that synthetic enzymes of SOD such as M40403, offer a novel therapeutic approach for the treatment of ischaemic heart disease where superoxide anion plays a dominant role.
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PMID:Protective effects of M40403, a selective superoxide dismutase mimetic, in myocardial ischaemia and reperfusion injury in vivo. 1211 Jun 15

A recently identified lectin-like oxidized low-density lipoprotein receptor (LOX-1) mediates endothelial cell injury and facilitates inflammatory cell adhesion. We studied the role of LOX-1 in myocardial ischemia-reperfusion (I/R) injury. Anesthetized Sprague-Dawley rats were subjected to 60 min of left coronary artery (LCA) ligation, followed by 60 min of reperfusion. Rats were treated with saline, LOX-1 blocking antibody JXT21 (10 mg/kg), or nonspecific anti-goat IgG (10 mg/kg) before I/R. Ten other rats underwent surgery without LCA ligation and served as a sham control group. LOX-1 expression was markedly increased during I/R (P < 0.01 vs. sham control group). Simultaneously, the expression of matrix metalloproteinase-1 (MMP-1) and adhesion molecules (P-selectin, VCAM-1, and ICAM-1) was also increased in the I/R area (P < 0.01 vs. sham control group). There was intense leukocyte accumulation in the I/R area in the saline-treated group. Treatment of rats with the LOX-1 antibody prevented I/R-induced upregulation of LOX-1 and reduced MMP-1 and adhesion molecule expression as well as leukocyte recruitment. LOX-1 antibody, but not nonspecific IgG, also reduced myocardial infarct size (P < 0.01 vs. saline-treated I/R group). To explore the link between LOX-1 and adhesion molecule expression, we measured expression of oxidative stress-sensitive p38 mitogen-activated protein kinase (p38 MAPK). The activity of p38 MAPK was increased during I/R (P < 0.01 vs. sham control), and use of LOX-1 antibody inhibited p38 MAPK activation (P < 0.01). These findings indicate that myocardial I/R upregulates LOX-1 expression, which through p38 MAPK activation increases the expression of MMP-1 and adhesion molecules. Inhibition of LOX-1 exerts an important protective effect against myocardial I/R injury.
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PMID:LOX-1 inhibition in myocardial ischemia-reperfusion injury: modulation of MMP-1 and inflammation. 1238 56

We report the case of a 34-year-old female patient who died 4 days after hospital admission of acute heart failure clinically mimicking ischemic heart disease. Microscopic examination of the heart showed severe myocarditis. Polymerase chain reaction (PCR), including quantitative real-time PCR, disclosed exclusively parvovirus B19 (PVB19), with a high viral load of 4.3x10(5) PVB19 viral genome equivalents per microg myocardial nucleic acid. Radioactive in situ hybridization detected viral genomes in endothelial cells (ECs) predominantly in the venular compartment and (to a lesser degree) in small arteries and arterioles of the heart, but not in cardiac myocytes or other tissue components. Concomitant with EC infection, marked expression of the adhesion molecule E-selectin was noted, accompanied by margination, adherence, penetration, and perivascular infiltration of T lymphocytes. We speculate that, due to the high viral load in cardiac ECs, PVB19 infection of endothelial cells was sufficient to induce impaired coronary microcirculation with secondary cardiac myocyte necrosis.
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PMID:Fatal parvovirus B19-associated myocarditis clinically mimicking ischemic heart disease: an endothelial cell-mediated disease. 1260 72

The relative role of different adhesion molecules in the ischemia-reperfusion injury after cardioplegic arrest in the clinical setting is unknown, because of protective effects of cardioplegia and hypothermia. The aim of this study is to determine the relationship between the method of the cardioplegia and endothelial derived soluble adhesion molecules; soluble vascular adhesion molecule-1 (sVCAM-1) and soluble intercellular adhesion molecule-1 (sICAM-1) in myocardial ischemia- reperfusion injury. Fourteen male patients who underwent aortocoronary bypass surgery with cardiopulmonary bypass were included in this study. They were randomised to be given blood or crystalloid cardioplegia for myocardial protection. Group I (n=7) received blood cardioplegia and group II (n=7) received crystalloid cardioplegia. The cross-clamp times were not significantly different between the two groups, 49.4+/-4.6 min for group I and 54.8+/-2.5 min for group II. Mean age of patients was 58+/-2.1 years for group I and 54+/-2.6 years for group II. Blood samples were taken from both the aorta and coronary sinuses of all patients before cross-clamp, after cross-clamping and at 30th min of reperfusion. Plasma were obtained from blood samples and then stored at -70 degrees C. sVCAM-1 and sICAM-1 levels were measured by ELISA in the samples. There were no significant differences in the levels of sICAM-1 and sVCAM-1 at the beginning of reperfusion and at 30th min of reperfusion in coronary sinus of group I patients. But, increased sICAM-1 and sVCAM-1 levels were observed at 30th min of reperfusion in blood taken from coronary sinuses of group II patients compared with beginning of reperfusion (respectively p=0.01, p=0.03). In conclusion, these results have shown that ischemia-reperfusion injury is more likely to occur in patients protected by crystalloid cardioplegia, and suggest that blood cardioplegia may be preferred especially in borderline myocardial functioned patients.
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PMID:The relationship between the method of cardioplegia and vascular endothelial cell derived soluble adhesion molecules in myocardial ischemia-reperfusion injury. 1266 54

A number of epidemiological studies have shown that diets rich in plant-derived phenolic compounds reduce the risk of coronary heart disease. The chronic antioxidant and hypolipidemic activities of these compounds have important roles in prevention of lipoprotein oxidation and atherosclerotic lesion development. In recent years, it has been recognized that inflammation is directly involved in development of cardiovascular disease and clinical events such as atherosclerotic plaque rupture (which is the trigger of acute coronary syndrome), arterial restenosis, and myocardial ischemia-reperfusion injury. Phenolic compounds have significant antiinflammatory effects, including inhibition of adhesion molecule, cytokine and chemokine gene expression; inhibition of platelet function; augmentation of endothelial nitric oxide release; suppression of smooth muscle activation; and other effects on proinflammatory factors such as endothelin and matrix metalloproteinases. However, direct evidence of acute therapeutic benefits of phenolic compounds in cardiovascular disorders remains sparse. This review attempts to integrate the inflammatory mechanisms involved in these cardiovascular diseases with recent findings on the antiinflammatory effects of phenolic compounds. Findings from the limited in vivo studies in this regard are discussed. It is suggested that searching for novel phenolic compounds with higher specificity and efficacy may represent a fruitful approach in development of new cardiovascular therapeutics.
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PMID:Natural phenolic compounds as cardiovascular therapeutics: potential role of their antiinflammatory effects. 1532 Aug 40

Inflammation is a recognized key component of acute coronary syndromes. Such pathogenetic achievement has led to the use of inflammatory cells and proteins as prognostic markers in these syndromes. A number of markers have been proposed, including proinflammatory cytokines such as interleukin-6, interleukin-1RA, and tumor necrosis factor-alpha, adhesion molecules such as intracellular adhesion molecule-1 and vascular adhesion molecule-1 and markers of cell activation. Although all are of scientific interest, the clinical use of these markers is limited by their high cost, low availability, and unfavorable biological profile. Conversely, common markers of inflammation such as C-reactive protein (CRP), the prototypic acute phase protein, and to a lesser extent fibrinogen, have been proven to be reliable and important markers of risk in ischemic heart disease. CRP, in particular, has been found to be associated with short- and long-term prognosis in acute coronary syndromes, including ST-elevation myocardial infarction, and in stable angina, and to predict the risk of restenosis and major events, including death, after revascularization procedures. CRP has been consistently found to be independent from other risk factors and to have an incremental value beyond the common risk factors and biochemical markers of risk, including troponin. Whether CRP also should be used as a guide to therapy is still a matter of discussion that deserves further, properly designed studies.
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PMID:CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: clinical use of inflammatory markers in patients with cardiovascular diseases: a background paper. 1561 82

During myocardial reperfusion injury, oxidative stress induces DNA damage and activation of the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1), resulting in cardiovascular dysfunction. In this study, we investigated the biological effects and the molecular mechanisms of two structurally unrelated selective inhibitors of PARP-1, 3-aminobenzamide (3-AB) and 1,5-dihydroxyisoquinoline (-DIQ), in an in vivo model of myocardial ischemia and reperfusion. Male Wistar rats were subjected to 30 min of occlusion followed by reperfusion (up to 24 h) of the left anterior descending coronary artery. In vehicle-treated rats, ischemia and reperfusion induced extensive myocardial damage and marked neutrophil infiltration (as indicated by myeloperoxidase activity). Caspase 3 was maximally activated within 15 to 30 min after reperfusion, suggesting the occurrence of apoptosis. These inflammatory events were associated with activation of the transcription factor activator protein-1 (AP-1) in the reperfused hearts. Treatment of the rats with the PARP-1 inhibitors, 3-AB or 1,5-DIQ, reduced myocardial damage, neutrophil infiltration, and caspase activation. This cardioprotection was associated with reduction of AP-1 activation. Furthermore, in in vitro cytokine-stimulated human endothelial cells, expression of intercellular adhesion molecule 1, vascular cellular adhesion molecule 1, and P- and E-selectin was significantly reduced by treatment with 3-AB or 1,5-DIQ. On the contrary, in vivo or in vitro treatment with nicotinic acid, a chemical analogue of PARP inhibitors, which lacks the ability to inhibit the catalytic activity of PARP-1, was unable to afford any protective effect and to prevent activation of AP-1. Our data demonstrate that inhibition of catalytic activity of PARP-1 may provide cardioprotection by regulating stress-induced signal transduction pathways.
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PMID:Inhibitors of poly (ADP-ribose) polymerase ameliorate myocardial reperfusion injury by modulation of activator protein-1 and neutrophil infiltration. 1571 20

Inflammation and leukocyte activation/infiltration play a major role in the initiation and progression of cardiovascular diseases including atherosclerosis and heart failure. Acute p38 mitogen-activated protein kinase (MAPK) pathway inhibition attenuates tissue damage and leukocyte accumulation in myocardial ischemia/reperfusion injury, although its effect on the acute phase of leukocyte recruitment has not been elucidated. The purpose of this study was to test the hypothesis that acute treatment of rats with a selective p38 inhibitor, SB-239063, inhibits ischemia/reperfusion-induced leukocyte-endothelial adhesion in vivo. Male Sprague-Dawley rats were treated with either SB-239063 (10 mgkg(-1)), dexamethasone (3 mgkg(-1)) or vehicle 1h prior to ischemia. Postcapillary venules were observed microscopically in exteriorized, superfused cremaster tissue. Leukocytes were fluorescently labeled in vivo using intravenous rhodamine 6G. Leukocyte adhesion, rolling, and rolling velocities were quantitated prior to 30 min ischemia, and at several time points during a 90 min reperfusion period. Ischemia caused a 3-fold increase in adherent leukocytes 5 min following reperfusion, a response that was maintained throughout the monitoring period (90 min) in vehicle-treated animals. SB-239063, at a dose known to inhibit p38 MAPK activity in vivo (10 mgkg(-1)), had no effect on ischemia/reperfusion-induced leukocyte adhesion, the number of rolling leukocytes, rolling velocities during the reperfusion period or adhesion molecule expression (P-, E-selectin, VCAM-1, ICAM-1). In contrast, dexamethasone completely blocked leukocyte adhesion in response to ischemia/reperfusion, and reduced expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). We conclude that p38 MAPK may not play a role in initial leukocyte recruitment in response to ischemia/reperfusion injury, but could affect leukocyte emigration, thereby resulting in increased leukocyte accumulation in ischemic-reperfused tissue.
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PMID:Role of p38 MAP kinase in postcapillary venule leukocyte adhesion induced by ischemia/reperfusion injury. 1574 61


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