CASPASES AND MYOCYTE APOPTOSIS IN THE PATHOGENESIS OF MI

大量研究表明，心肌梗死(MI)时会发生心肌细胞凋亡。尽管有这些观察，该领域最关键的问题仍然没有确定：心肌细胞凋亡在多大程度上有助于心肌梗死特征的心肌结构和功能的变化？半胱氨酸蛋白酶是一个新的半胱氨酸蛋白酶家族，是所有后生动物细胞凋亡的最终共同途径。的确，申请人S的初步数据显示，阻断半胱氨酸天冬氨酸酶的激活显着抑制体内心肌细胞的凋亡。这一结果的意义在于，caspase抑制为确定心肌细胞凋亡在MI发病机制中的作用提供了一种手段。因此，我们提出了以下目标：1.确定抑制心肌细胞凋亡对心肌梗死后心肌梗死面积、左心室扩大和收缩功能障碍的影响。利用互补的药理学和基因抗caspase策略将抑制心肌细胞的凋亡，并将评估抑制凋亡对MI后左室大小和功能预期变化的影响。2.确定半胱氨酸天冬氨酸氨基转移酶(Caspase)激活是否足以在活体内引起左心室扩张和收缩功能障碍。一种由惰性配体严格控制其活性的嵌合caspase将在转基因小鼠的心脏中表达，并将在caspase激活后分析左心室大小和功能的变化。综上所述，该研究计划将明确心肌细胞凋亡在心肌梗死发病机制中的作用。通过这样做，这些研究可能为基于细胞凋亡抑制的缺血性心脏病的新疗法提供概念框架。

Numerous studies have demonstrated the occurrence of myocyte apoptosis during myocardial infarction (MI). Despite these observations, the most critical question in the field remains undefined: To what extent does myocyte apoptosis contribute to the changes in myocardial structure and function that characterize MI? The caspases, a novel family of cysteine proteases, constitute the final common pathway for apoptosis in all metazoan cells. Indeed the applicant s preliminary data show that blockade of caspase activation markedly inhibits cardiac myocyte apoptosis in vivo. The significance of this result is that caspase inhibition provides a means to determine the contribution of myocyte apoptosis to the pathogenesis of MI. Accordingly, the following aims are proposed: 1. To determine the effect of inhibiting myocyte apoptosis on infarct size, left ventricular dilatation, and systolic dysfunction following MI. Cardiac myocyte apoptosis will be inhibited using complementary pharmacologic and genetic anti-caspase strategies and the effect of apoptosis inhibition on the expected changes in left ventricular size and function post-MI will be assessed. 2. To determine the sufficiency of caspase activation to induce left ventricular dilatation and systolic dysfunction in vivo. A chimeric caspase whose activation is tightly controlled by an otherwise inert ligand will be expressed in the hearts of transgenic mice and changes in left ventricular dimensions and function will be analyzed following caspase activation. Taken together, this research program will define the role of cardiac myocyte apoptosis in the pathogenesis of MI. In so doing, these studies may provide the conceptual framework for novel therapies for ischemic heart disease based on apoptosis inhibition.