APOPTOSIS AND CONTRACTILITY IN ISCHEMIC CARDIOMYOPATHY

缺血性心肌病中的细胞凋亡和收缩

• 批准号: 6490628
• 负责人: John M Canty
• 金额: $ 40.66万
• 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/6490628
• 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.

缺血性心肌病是心力衰竭最常见的病因，但引发失代偿性左室功能障碍的因素尚不清楚。尽管大量的工作集中在梗死后的不可逆损伤上，但许多患者的心衰症状与功能障碍或“冬眠”心肌有关。病理研究支持这样一种观点，即功能障碍的程度经常超过死后检查发现的结构性纤维化的数量。申请人的初步研究再现了慢性LAD狭窄猪冬眠心肌的生理特征。虽然这种情况发生在左室功能正常且无梗死的情况下，但在3个月后，局部心肌细胞凋亡增加，心肌细胞损失30%，代偿性心肌细胞肥大。在分子水平上，SR钙摄取蛋白存在区域下调。这些变化由可逆性缺血（即心绞痛）引起，整体左室功能正常，与终末期心力衰竭的异常相同。因此，这项应用的总体假设是，心肌细胞凋亡和SR功能障碍发生在慢性冠状动脉血流储备减少的区域，是缺血性心肌病发病的早期而不是晚期事件。目的1将明确细胞凋亡介导的心肌细胞损失和左室重构在冬眠心肌可逆性缺血中的作用。一个2血管狭窄模型，随着左室扩张和左室充盈压力增加而发展为整体左室功能障碍，将用于确定舒张拉伸和功能障碍区域的大小如何调节细胞凋亡和左室重塑。目的2将确定缺血和正常区域中细胞凋亡的时间进展与促凋亡和抗凋亡蛋白Bax和Bcl-2的表达有关，这将在体内以区域为基础进行量化。目的3将确定细胞凋亡介导的肌细胞损失和SR蛋白表达改变在多大程度上影响手术血管重建术和碱性成纤维细胞生长因子（FGF-5）刺激血管生成后冬眠心肌功能的可逆性。目的4将确定β阻断是否可以在药理学上阻止细胞凋亡和SR蛋白表达的改变，通过在肌细胞损失发生之前刺激血管生成和在体内过度表达Bcl-2。当血运重建和体内基因转移等治疗干预措施可用于中断进行性肌细胞丧失、收缩功能障碍和不可逆的结构性纤维化时，这种综合方法应能更好地理解导致缺血性左室功能障碍进展的事件。