Ca2+-Influx Regulated Cardiac Hypertrophy, Arrhythmia and Myocyte Apoptosis

描述（由申请人提供）：心律失常和泵衰竭是美国死亡率和发病率的主要原因。心肌肥厚合并心律失常是对血流动力学应激如高血压和心肌梗死的常见初始反应。持续的血流动力学压力导致失代偿性心力衰竭。在早期和代偿性肥厚期间肾上腺素能驱动增强刺激的收缩性增加是通过增强细胞内Ca2+循环，包括通过l型Ca2+通道增加的Ca2+内流（Cavl.2）带来的。然而，cav1 .2在心脏病进展中的作用尚不清楚。我们假设Ca2+内流的增加有助于心脏肥厚、心律失常和心肌细胞凋亡的发展，最终导致心力衰竭。这一假设将在我们新建立的高或低水平过表达Cavl.2的beta2a亚基的转基因（TG）小鼠系中得到验证。我们的初步数据表明，低表达TG的小鼠出现心脏性猝死和肥厚，而高表达TG的小鼠出现心力衰竭症状。血流动力学应激在低表达TG小鼠中引起心力衰竭，在高表达TG小鼠中加速心力衰竭的发生。具体目标是：1。为了确定Ca2+内流的增加（用低水平表达Cavl.2beta2a的转基因小鼠系）是否足以增加心脏收缩力，但不诱导SR Ca2+过载，可以诱导心肌细胞肥大而不引起细胞凋亡。2. 为了确定Ca2+内流的增加（高水平表达Cavl.2beta2a的转基因小鼠系）是否足以引起SR Ca2+过载诱导心律失常和心肌细胞凋亡，导致心力衰竭，心泵功能下降，然而，心肌细胞收缩力增加。这些研究将验证肌细胞凋亡的激活需要CaMK II依赖性Ca2+调节蛋白的磷酸化。3. 确定Ca2+内流增加（低表达和高表达Cavl.2beta2a的转基因小鼠系）是否加剧/逆转血流动力学应激（主动脉束带和异丙肾上腺素输注）对心脏泵功能和心力衰竭发展的不利影响。Cavl.2beta2a基因会在压力源引入之前或之后被激活。长期目标是确定治疗心脏病的新目标或策略。

DESCRIPTION (provided by applicant): Cardiac arrhythmia and pump failure are the leading causes of mortality and morbidity in the United States. Cardiac hypertrophy associated with arrhythmia is the common initial response to hemodynamic stress such as hypertension and myocardial infarction. Sustained hemodynamic stress leads to decompensated heart failure. Increased contractility stimulated by heightened adrenergic drive during early and compensated hypertrophy is brought about by enhancing intracellular Ca2+ cycling, including increased Ca2+ influx through the L-type Ca2+ channel (Cavl.2). However, the role of Cavl.2 in the progress of heart disease is not well understood. We hypothesize that increases in Ca2+ influx contribute to the development of cardiac hypertrophy, arrhythmia and myocyte apoptosis, which ultimately lead to heart failure. This hypothesis will be tested with our newly established transgenic (TG) mouse lines overexpressing the beta2a subunit of Cavl.2 at low or high levels. Our preliminary data show that low expression TG mice develop sudden cardiac death and hypertrophy while high expression TG mice have heart failure symptoms. Hemodynamic stress causes heart failure in low expression TG mice and precipitates the onset of heart failure in high expression TG mice. The specific aims are: 1. To determine if increases in Ca2+ influx (with a transgenic mouse line with low level expression of Cavl.2beta2a) that are sufficient to increase cardiac contractility, but do not induce SR Ca2+ overload, can induce myocyte hypertrophy without causing apoptosis. 2. To determine if increases in Ca2+ influx (transgenic mouse line with high level expression of Cavl.2beta2a) that are sufficient to cause SR Ca2+ overload induce cardiac arrhythmias and myocyte apoptosis, causing heart failure with depressed cardiac pump function, however, with increased myocyte contractility. These studies will test the idea that activation of myocyte apoptosis requires a CaMK II dependent phosphorylation of Ca2+ regulatory proteins. 3. To determine if increased Ca2+ influx (transgenic mouse lines with low and high expression of Cavl.2beta2a exacerbates/reverses the adverse effects of hemodynamic stress (aortic banding and isoproterenol infusion) on cardiac pump function, and the development of heart failure. The Cavl.2beta2a gene will be turned on either before or after the introduction of stressors. The long-term goal is to identify new targets or strategies for treating heart disease.