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

• 批准号: 7459040
• 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
• 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/7459040
• 关键词: Adrenergic Agents; Adult; Adverse effects; Aortic Valve Stenosis; Apoptosis; Apoptotic; Arrhythmia; Atrial Natriuretic Factor; 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; Personal Satisfaction; Phenotype; Phosphorylation; Phosphotransferases; Play; Primary Cell Cultures; Protein Overexpression; 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; programs; research study; response; stressor; sudden cardiac death

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）：心律不齐和泵衰竭是美国死亡率和发病率的主要原因。与心律不齐相关的心脏肥大是对高血压和心肌梗死等血液动力学应激的常见初始反应。持续的血液动力学胁迫导致心力衰竭的代偿性。通过提高细胞内Ca2+循环的增强，在早期和补偿肥大中刺激的收缩力增加，包括通过L型Ca2+通道（Cavl.2）增加Ca2+涌入。但是，Cavl.2在心脏病进展中的作用尚不清楚。我们假设Ca2+涌入的增加有助于心脏肥大，心律不齐和心肌细胞凋亡的发展，这最终导致心力衰竭。该假设将通过我们新建立的转基因（TG）小鼠系进行测试，该系数过表达Cavl.2在低水平或高水平下的beta2a亚基。我们的初步数据表明，低表达TG小鼠会出现心脏猝死和肥大，而高表达TG小鼠患有心力衰竭症状。血液动力学应激会导致低表达TG小鼠的心力衰竭，并沉淀出高表达TG小鼠心力衰竭的发作。具体目的是：1。确定Ca2+流入的增加（具有cavl.2beta2a的低水平表达的转基因小鼠线）是否足以增加心脏收缩性，但不会诱导SR Ca2+过载，可以诱导心肌细胞肥大而不会引起凋亡。 2。确定Ca2+流入的增加（具有高水平CAVL.2BETA2A的转基因小鼠线）是否足以引起SR Ca2+过载诱导心律失常和心肌细胞凋亡，从而导致心脏衰竭，导致心脏泵功能抑郁，但是，心脏泵功能降低，但是，肌细胞肌细胞的收缩率增加。这些研究将检验以下观点，即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CAVL的低表达和高表达的CAVL.2BETA2A加剧/逆转血液动力学应激（主动脉谱带和异丙肾上腺素输注）对心脏泵功能的不利影响/逆转心脏失效的不良反应，cavl.2beta2a Gene的发展范围或引入范围。治疗心脏病的策略。