APOPTOSIS AND CONTRACTILITY IN ISCHEMIC CARDIOMYOPATHY

缺血性心肌病中的细胞凋亡和收缩

• 批准号: 6045626
• 负责人: John M Canty
• 金额: $ 38.72万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-10 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6045626
• 关键词: BCL2 gene /protein; Bax gene /protein; apoptosis; beta antiadrenergic agent; cardiac myocytes; disease /disorder etiology; fibroblast growth factor; fibrosis; heart contraction; heart ventricle; myocardial ischemia /hypoxia; myocardium disorder; swine

Ischemic cardiomyopathy is the most common etiological cause of heart failure but the factors responsible for initiating decompensated LV dysfunction are unknown. Although considerable work has focused on irreversible injury following infarction, many patients have symptoms of heart failure in association with viable dysfunctional or "hibernating" myocardium. Pathological studies support the notion that the degree of dysfunction frequently exceeds the amount of structural fibrosis identified at postmortem exam. Preliminary studies by the applicant have reproduced the physiological features of hibernating myocardium in pigs with a chronic LAD stenosis. While this occurs with normal LV function and without infarction, there is increased regional myocyte apoptosis, a 30 percent loss of myocytes and compensatory myocyte hypertrophy after a period of 3 months. At the molecular level, there is a regional downregulation of SR calcium uptake proteins. These changes, arising from reversible ischemia (i.e. angina pectoris) and with normal global LV function, are identical to the abnormalities found in end-stage heart failure. Thus, the overall hypothesis of this application is that myocyte apoptosis and SR dysfunction arise in areas with chronically reduced coronary flow reserve and are early rather than late events in the pathogenesis of ischemic cardiomyopathy. Aim 1 will define the role of apoptosis mediated myocyte loss and LV remodeling from reversible ischemia in hibernating myocardium. A 2-vessel stenosis model that progresses to global LV dysfunction with LV dilatation and increased LV filling pressure will be used to determine how diastolic stretch and the size of the dysfunctional region modulates apoptosis and LV remodeling. Aim 2 will identify the temporal progression of apoptosis in ischemic and normal regions in relation to the expression of the pro- and anti-apoptotic proteins Bax and Bcl-2 which will be quantified in vivo on a regional basis. Aim 3 will define the extent that apoptosis mediated myocyte loss and altered SR protein expression affects the reversibility of function in hibernating myocardium after surgical revascularization and after stimulating angiogenesis with basic fibroblast growth factor (FGF-5). Aim 4 will determine whether apoptosis and altered SR protein expression can be prevented pharmacologically with beta blockade, by stimulating angiogenesis prior to the development of myocyte loss and by overexpressing Bcl-2 in vivo. This integrative approach should provide a better understanding of the events that lead to the progression of ischemic LV dysfunction at a time when therapeutic interventions such as revascularization and in vivo gene transfer can be used to interrupt the progressive myocyte loss, contractile dysfunction and irreversible structural fibrosis.

Ischemic cardiomyopathy is the most common etiological cause of heart failure but the factors responsible for initiating decompensated LV dysfunction are unknown. Although considerable work has focused on irreversible injury following infarction, many patients have symptoms of heart failure in association with viable dysfunctional or "hibernating" myocardium. Pathological studies support the notion that the degree of dysfunction frequently exceeds the amount of structural fibrosis identified at postmortem exam. Preliminary studies by the applicant have reproduced the physiological features of hibernating myocardium in pigs with a chronic LAD stenosis. While this occurs with normal LV function and without infarction, there is increased regional myocyte apoptosis, a 30 percent loss of myocytes and compensatory myocyte hypertrophy after a period of 3 months. At the molecular level, there is a regional downregulation of SR calcium uptake proteins. These changes, arising from reversible ischemia (i.e. angina pectoris) and with normal global LV function, are identical to the abnormalities found in end-stage heart failure. Thus, the overall hypothesis of this application is that myocyte apoptosis and SR dysfunction arise in areas with chronically reduced coronary flow reserve and are early rather than late events in the pathogenesis of ischemic cardiomyopathy. Aim 1 will define the role of apoptosis mediated myocyte loss and LV remodeling from reversible ischemia in hibernating myocardium. A 2-vessel stenosis model that progresses to global LV dysfunction with LV dilatation and increased LV filling pressure will be used to determine how diastolic stretch and the size of the dysfunctional region modulates apoptosis and LV remodeling. Aim 2 will identify the temporal progression of apoptosis in ischemic and normal regions in relation to the expression of the pro- and anti-apoptotic proteins Bax and Bcl-2 which will be quantified in vivo on a regional basis. Aim 3 will define the extent that apoptosis mediated myocyte loss and altered SR protein expression affects the reversibility of function in hibernating myocardium after surgical revascularization and after stimulating angiogenesis with basic fibroblast growth factor (FGF-5). Aim 4 will determine whether apoptosis and altered SR protein expression can be prevented pharmacologically with beta blockade, by stimulating angiogenesis prior to the development of myocyte loss and by overexpressing Bcl-2 in vivo. This integrative approach should provide a better understanding of the events that lead to the progression of ischemic LV dysfunction at a time when therapeutic interventions such as revascularization and in vivo gene transfer can be used to interrupt the progressive myocyte loss, contractile dysfunction and irreversible structural fibrosis.