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。心脏肥大伴心律失常是高血压、心肌梗死等血流动力学应激的常见初始反应。持续的血流动力学应激导致失代偿性心力衰竭。在早期和代偿性肥大期间由增强的肾上腺素能驱动刺激的增加的收缩性是通过增强细胞内Ca 2+循环引起的，包括通过L型Ca 2+通道增加的Ca 2+内流（Cavl.2）。然而，Cavl.2在心脏病进展中的作用还没有得到很好的理解。我们推测Ca 2+内流的增加有助于心脏肥大、心律失常和心肌细胞凋亡的发展，最终导致心力衰竭。该假设将用我们新建立的以低或高水平过表达Cavl. 2的β 2a亚基的转基因（TG）小鼠系进行测试。我们的初步数据表明，低表达TG小鼠发生心脏性猝死和心肌肥厚，而高表达TG小鼠则出现心力衰竭症状。血液动力学应激导致低表达TG小鼠心力衰竭，并促使高表达TG小鼠心力衰竭发作。具体目标是：1.确定足以增加心肌收缩力但不诱导SR Ca 2+过载的Ca 2+内流增加（使用Cav1.2 β 2a低水平表达的转基因小鼠系）是否可以诱导肌细胞肥大而不引起细胞凋亡。2.为了确定足以引起SR Ca 2+过载的Ca 2+内流（具有高水平表达Cavl.2 β 2a的转基因小鼠系）的增加是否诱导心律失常和肌细胞凋亡，从而引起心力衰竭伴心脏泵功能降低，然而伴肌细胞收缩性增加。这些研究将测试的想法，激活心肌细胞凋亡需要Ca 2+调节蛋白的CaMK II依赖磷酸化。3.为了确定增加的Ca 2+内流（具有Cavl.2 β 2a的低和高表达的转基因小鼠系）是否加剧/逆转血液动力学应激（主动脉缩窄和异丙肾上腺素输注）对心脏泵功能的不利影响以及心力衰竭的发展。Cavl.2beta2a基因将在引入应激物之前或之后被打开。长期目标是确定治疗心脏病的新靶点或策略。

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.