Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Programmed cell death in the myocardium has been linked to ischemia reperfusion injury as well as to excessive mechanical forces associated with increases in ventricular loading. Moreover, hypoxia activates the suicide program of cardiac myocytes in vitro. Because the supplied portion of the ventricular wall is ischemic and subjected to high levels of systolic and diastolic stresses (acutely after coronary artery occlusion), apoptosis and necrosis may contribute independently to myocyte cell death after infarction. Therefore, myocardial infarction was produced in rats, and, after the determination of ventricular hemodynamics, the contribution of apoptotic and/or necrotic myocyte cell death to infarct size was measured quantitatively from 20 minutes to 7 days after coronary artery occlusion. Programmed cell death was assessed by the terminal deoxynucleotidyl transferase assay and by the electrophoretic detection of DNA laddering. Myocyte necrosis was evaluated by myosin monoclonal Ab labeling. Moreover, the expression of Bcl-2, Bax, and Fas proteins in myocytes was examined by immunocytochemistry. Myocyte cell death by apoptosis and necrosis comprised nearly 3 million myocytes at 2 hours. Apoptotic cell death involved 2.8 million cells and necrotic cell death only 90,000 myocytes. Apoptosis continued to represent the major independent form of myocyte cell death, affecting 6.6 million myocytes at 4.5 hours. Myocyte necrosis peaked at 1 day, including 1.1 million myocytes. DNA electrophoretic analysis confirmed these observations by showing nucleosomal ladders at 2-3 hours, 4.5 hours, 1 day, and 2 days after coronary artery occlusion. Myocytes showing both DNA strand breaks and myosin labeling were a prominent aspect of myocardial damage only after 6 hours. Finally, the expression of Bcl-2 and Fas in myocytes increased 18-fold and 131-fold, respectively. In conclusion, programmed myocyte cell death is the major form of myocardial damage produced by occlusion of a major epicardial coronary artery, whereas necrotic myocyte cell death follows apoptosis and contributes to the progressive loss of cells with time after infarction. The enhanced expression of Fas may be implicated in the activation of apoptosis in spite of the increase in Bcl-2, which tends to preserve cell survival.
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PMID:Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. 856 1

1. Over 100 different agents have been shown, under certain circumstances, to cause apoptosis, a form of cell death with characteristic morphology. In most cases, the mechanism of cell death is likely to be the same, as expression of the cell death inhibitory gene bcl-2 can frequently prevent apoptotic changes and/or delay cell death. 2. These observations raise the question of how and why cells detect these agents and why they respond by implementing the suicide mechanism that bcl-2 can control. Our hypothesis is that apoptosis is used as an anti-viral strategy, and that cells interpret any metabolic disturbance as evidence of infection by a virus and thereby kill themselves in response to these toxins before they are killed by the action of the toxin itself. 3. Experiments on the effect of sodium azide upon growth factor-dependent cells support this idea. Bcl-2 can delay cell death caused by azide, and inhibit apoptotic changes seen by electron microscopy, but cannot prevent the eventual death of the cells. 4. These ideas suggest that drugs designed to regulate cell death may be useful for the treatment of ischaemic or neoplastic diseases. For example, human cells may activate a suicide pathway in response to sub-lethal amounts of anoxia following a stroke or heart attack and so blocking apoptosis may be a useful therapy to limit tissue damage. On the other hand, increasing the propensity of cells to activate their physiological cell death mechanisms may enhance the effectiveness of toxins designed to kill tumour cells.
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PMID:Hypothesis: apoptosis caused by cytotoxins represents a defensive response that evolved to combat intracellular pathogens. 859 45

In the last three years, apoptosis has been reported to be associated with cell death in ischemic heart diseases, for examples, acute ischemic cardiomyocyte death in acute myocardial infarction; death of the salvaged cardiomyocytes in old myocardial infarction; death of infiltrated leukocytes and granulation tissue cells after myocardial infarction. Apoptosis-related proteins such as Bcl-2, Bax and Fas are expressed in the salvaged cardiomyocytes edging the infarct area. In vitro experiment using cultured cardiomyocytes suggested hypoxia causes apoptosis in them. Thus, apoptosis may play important roles in ischemic heart diseases. For detecting apoptosis, however, all of the previous studies on acute ischemic cardiomyocyte death depended exclusively on DNA fragmentation (biochemical marker of apoptosis) by a DNA ladder on gel electrophoresis and in situ nick end labeling (TUNEL), but never documented the ultrastructural changes characteristic of apoptosis (morphological marker of apoptosis). Then, we examined the ultrastructure and DNA fragmentation of cardiomyocytes in rabbit myocardial infarction using electron microscopy combined with TUNEL (EM-TUNEL) which allows simultaneous observation of both markers in the same cell. Rabbits underwent 30-min ischemia followed by 0-, 30-min, 2-, 4- and 24-h reperfusion of a left coronary artery. In the infarcted tissue, EM-TUNEL revealed oncotic necrosis of cardiomyocytes with or without DNA fragmentation in the 2-h, 4-h, and 24-h reperfusion groups, but no apoptotic cardiomyocytes in ultrastructure in any groups. Thus, so-called apoptotic cardiomyocytes after ischemia/reperfusion may belong to a different category from apoptosis.
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PMID:[Ischemic heart disease and apoptosis]. 925 5

It has been reported that programmed cell death (apoptosis) occurs during myocardial infarction. The influence of age on programmed cell death or DNA fragmentation after coronary occlusion has not been extensively characterized. To test the hypothesis that there are age-related differences in susceptibility to DNA fragmentation during ischemia-infarction, we studied DNA fragmentation in young adult and old male F344 rat hearts after acute coronary artery occlusion. Hearts were studied at 1, 3, and 5 h and 1 and 7 days after coronary ligation. The percentage of apoptotic cells was determined by the in situ end-labeling technique, and internucleosomal fragmentation (DNA laddering) pattern was also analyzed. Our results show that 1) DNA fragmentation began earlier and peaked earlier in the old compared with young adult hearts during infarction; 2) there was heightened expression of both Bcl-2 and Bax in the old hearts at baseline; and 3) the Bcl-2-to-Bax ratio was higher in the older heart after coronary ligation. These results suggest that, compared with the young adult heart, the aged heart may be more susceptible to ischemia-induced DNA fragmentation.
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PMID:Bcl-2 and Bax expression in adult rat hearts after coronary occlusion: age-associated differences. 968 94

Ischemia and reperfusion injure the heart, as manifested by myocardial infarction, postischemic ventricular functional dysfunctions, arrhythmias, and cardiomyocyte apoptosis. Hearts can be adapted to ischemic-reperfusion injury by subjecting them to non-lethal cyclic episodes of short-term ischemia and reperfusion. The adapted myocardium becomes resistant to subsequent lethal ischemic injury. Reactive oxygen species and oxidative stress play crucial roles in the pathophysiology of ischemic-reperfusion injury. The adapted hearts, when subjected to subsequent ischemia and reperfusion, generate a reduced amount of oxygen free radicals compared to the nonadapted hearts. The number of cardiomyocytes undergoing apoptotic cell death is reduced in the adapted hearts subjected to ischemia and reperfusion. In concert, the adapted myocardium is associated with increased antioxidant gene Bcl-2, increased binding activity of the nuclear transcription factor NF kappa B, and reduced binding activity of AP-1 compared to nonadapted hearts. Yet when nonadapted hearts are subjected to ischemia and reperfusion, Bcl-2 is down-regulated while NF kappa B is moderately upregulated and AP-1 is significantly upregulated.
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PMID:Differential regulation of apoptosis by ischemia-reperfusion and ischemic adaptation. 1041 50

Ischemic preconditioning (IPC) refers to the ability of short periods of ischemia to make the myocardium more resistant to a subsequent ischemic insult. It is the most powerful form of endogenous protection against myocardial infarction and has been demonstrated in all species evaluated to date. However, the cellular mechanisms that drive IPC remain poorly understood. This hypothesis describes an important role for alpha(1)-adrenoreceptors in mediating IPC and discusses the underlying mechanisms by which this is likely achieved. alpha(1)-Adrenoreceptors are present in the myocardium of all mammalian species, and several lines of evidence suggest that they play an important role in mediating IPC. During periods of myocardial hypoxia/ischemia, cardiomyocytes have to rely solely on anaerobic glycolysis for energy production; for this, the cells have to depend on increased glucose entry inside the cell as well as increased glycolysis. Stimulation of alpha(1)-adrenoreceptors increases glucose transport inside the cardiomyocytes by translocating glucose transporter (GLUT)-1 and GLUT-4 from the cytoplasm to the plasma membrane, enhances glycogenolysis by activating phosphorylase kinase, increases the rate of glycolysis by activating the enzyme phosphofructokinase, reduces intracellular acidity produced during excessive glycolysis by activating the Na(+)/H(+) exchanger, and inhibits apoptosis by increasing the levels of the antiapoptotic protein Bcl-2. Myocardial ischemia produces an increase in the expression of alpha(1)-adrenoreceptors in cardiomyocytes, as well as increases the levels of its agonist norepinephrine by several fold. During ischemic states, upregulation of alpha(1)-adrenoreceptors and increase in norepinephrine release could be a powerful adaptive mechanism that drives IPC. An understanding into the role of alpha(1)-adrenoreceptors in mediating IPC could not only point to newer treatments for limiting myocardial damage during myocardial infarction or heart surgery, but could also help in avoiding the use of alpha(1)-antagonists in patients with ischemic heart disease.
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PMID:Protecting the myocardium from ischemic injury: a critical role for alpha(1)-adrenoreceptors? 1129 92

Since apoptosis was described as a process distinct from necrosis, there have been many studies of programmed cell death in diseases, especially immunological diseases. Because cardiac myocytes are terminally differentiated cells, they have typically been assumed to die exclusively by necrosis. However, during the last six to seven years this view has been challenged by several studies demonstrating that a significant number of myocytes undergo apoptosis in myocardial infarction, heart failure, myocarditis, arrhythmogen right ventricular dysplasia, and immune rejection after cardiac transplantation, as well as in other conditions of stress. These are potentially very important observations, because apoptosis--unlike necrosis--can be blocked or reversed at early stages. The tracking of cytoprotective and apoptotic signal transduction pathways has proceeded rapidly with important new insights into the roles of mitochondria-dependent pathway, Bcl-2 protein family, p38 mitogen-activated protein kinase, extracellular signal-regulated kinase and c-Jun N-terminal kinase in cell fate. New studies have demonstrated that specific inhibition of apoptosis and activation of cytoprotective mechanisms, based on the better understanding of the intracellular signaling pathways, can significantly protect cardiac myocytes. This review will assess progress in cardiac myocyte apoptosis research and report on the current status of anti-apoptotic therapy in acute and chronic heart diseases.
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PMID:[Molecular regulation of myocardial apoptosis]. 1157 6

Cardiovascular disease is a leading cause of death worldwide. In recent years it has emerged that loss of myocardial cells may be a major pathogenic factor. Cell death can occur in a destructive, uncontrolled manner via necrosis or by a highly regulated programmed cell suicide mechanism termed apoptosis. As cell death in conditions such as heart failure and myocardial infarction does not always follow a typically apoptotic pathway, it remains to be established whether it occurs by apoptosis, necrosis, or a novel uncharacterized mechanism combining aspects of both types of cell death. Apoptotic pathways have been well studied in nonmyocytes and it is thought that similar pathways exist in cardiomyocytes. These pathways include death initiated by ligation of membrane-bound death receptors or death initiated by release of cytochrome c from mitochondria. Increasing evidence supports the existence of these pathways and their regulators in the heart. These regulators include inhibitors of caspases, which are the key enzymes of apoptosis, the Bcl-2 family of proteins, growth factors, stress proteins, calcium, and oxidants. It is hoped that a better understanding of the pathways of apoptosis and their regulation may yield novel therapeutic targets for cardiovascular disease.
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PMID:Losing heart: the role of apoptosis in heart disease--a novel therapeutic target? 1181 61

Although the mechanisms that underlie cardiac cell death remain cryptic, there is emerging evidence that mitochondria may play a pivotal role in this process. The mitochondrion initially deemed the "power house " is now considered to be a central integration site for biological signals that promote cell life or cell death. Since mitochondria contain the necessary apoptotic machinery to activate the cell-death pathway, it is now appreciated that mitochondria play a key decision-making role in whether a cell will live or die following a noxious signal-literally a "license to kill ". Permeability changes to the outer mitochondrial membrane, collapse of membrane potential, permeability pore complex assembly, release of cytotoxic proteins and caspase activation are associated with the mitochondrial-death pathway. Members of the Bcl-2 gene family can promote or suppress cell death by modulating mitochondrial function. Activation of the mitochondrial-death pathway has been reported in several cardiac pathologies and believed to account for the reported apoptosis observed in these disease entities. Given the meager and limited ability of cardiac muscle for repair or self-renewal after injury, the inordinate loss of cardiac cells is considered to be a key underlying factor in ventricular remodeling and decline in ventricular performance in patients with ischemic heart disease or post-myocardial infarction. This review will provide mechanistic insight into the involvement and contribution of the mitochondrion as a regulator of cell death in health and disease with particular focus on the heart.
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PMID:Mitochondria-assisted cell suicide: a license to kill. 1278 72

Adrenomedullin (AM) has been shown to protect against cardiac remodeling. In this study, we investigated the potential role of AM in myocardial ischemia-reperfusion (I/R) injury through adenovirus-mediated gene delivery. One week after AM gene delivery, rats were subjected to 30-min coronary occlusion, followed by 2-h reperfusion. AM gene transfer significantly reduced the ratio of infarct size to ischemic area at risk and the occurrence of sustained ventricular fibrillation compared with control rats. AM gene delivery also attenuated apoptosis, assessed by both terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and DNA laddering. The effect of AM gene transfer on infarct size, arrhythmia, and apoptosis was abolished by an AM antagonist, calcitonin gene-related peptide [CGRP(8-37)]. Expression of human AM significantly increased cardiac cGMP levels and reduced superoxide production, superoxide density, NAD(P)H oxidase activity, p38 MAPK activation, and Bax levels. Moreover, AM increased Akt and Bad phosphorylation and Bcl-2 levels, but decreased caspase-3 activation. These results indicate that AM protects against myocardial infarction, arrhythmia, and apoptosis in I/R injury via suppression of oxidative stress-induced Bax and p38 MAPK phosphorylation and activation of the Akt-Bad-Bcl-2 signaling pathway. Successful application of this technology may have a protective effect in coronary artery diseases.
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PMID:Adrenomedullin gene delivery attenuates myocardial infarction and apoptosis after ischemia and reperfusion. 1280 25


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