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

Ca2 流入调节心脏肥大、心律失常和心肌细胞凋亡

基本信息

批准号：
7807164
负责人：
Xiongwen Chen
金额：
$ 37.5万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7807164
关键词：
Adrenergic Agents Adult Adverse effects Aortic Valve Stenosis Apoptosis Apoptotic Arrhythmia Calcineurin Calcium Calcium/calmodulin-dependent protein kinase Calmodulin Cardiac Cardiac Myocytes Cardiac Output Cell Volumes Cessation of life Data Depressed mood Development Evolution Failure Generations Genes Genetic Goals HDAC5 gene Heart Heart Diseases Heart Hypertrophy Heart failure Hypertension Hypertrophy Individual Infusion procedures Isoproterenol Lead Link Mediating Morbidity - disease rate Mus Muscle Cells Myocardial Infarction Myocardium Pathway interactions Phenotype Phosphorylation Phosphotransferases Play Primary Cell Cultures Pump Research Research Personnel Role Sarcoplasmic Reticulum Signal Pathway Signal Transduction Stress Symptoms Testing Time Transgenic Mice Transgenic Organisms United States Ventricular Work adrenergic genetic regulatory protein hemodynamics improved in vivo mortality mouse model overexpression programs research study response stressor sudden cardiac death

项目摘要

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.

描述（由申请人提供）：心律失常和泵衰竭是美国死亡和发病的主要原因。与心律失常相关的心脏肥大是对高血压和心肌梗塞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，肾上腺素能驱动增强所刺激的收缩性增加是通过增强细胞内Ca 2+ 循环来实现的，包括增加通过L型Ca 2+ 通道的Ca 2+ 流入(Cavl.2)。然而，Cavl.2在心脏病进展中的作用尚不清楚。我们假设 Ca2+ 流入的增加会导致心脏肥大、心律失常和心肌细胞凋亡，最终导致心力衰竭。该假设将用我们新建立的转基因（TG）小鼠品系进行测试，这些小鼠品系以低水平或高水平过度表达Cavl.2的β2a亚基。我们的初步数据显示，低表达TG小鼠会出现心源性猝死和肥大，而高表达TG小鼠则出现心力衰竭症状。血流动力学应激导致低表达 TG 小鼠心力衰竭，并加速高表达 TG 小鼠心力衰竭的发作。具体目标是： 1. 确定Ca2+流入的增加（使用具有低水平表达Cavl.2beta2a的转基因小鼠系）是否足以增加心肌收缩力，但不诱导SR Ca2+超载，是否可以诱导心肌细胞肥大而不引起心肌细胞肥大。引起细胞凋亡。 2.确定Ca2+流入的增加（具有高水平表达Cavl.2beta2a的转基因小鼠系）是否足以引起SR Ca2+超负荷诱导心律失常和心肌细胞凋亡，导致心力衰竭并导致心脏泵功能下降，然而，肌细胞的收缩力。这些研究将检验心肌细胞凋亡的激活需要 CaMK II 依赖性 Ca2+ 调节蛋白磷酸化的观点。 3. 确定增加的Ca2+流入（具有低和高表达Cavl.2beta2a的转基因小鼠品系）是否会加剧/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基因将在压力源引入之前或之后开启。长期目标是确定治疗心脏病的新靶点或策略。