Ca^2+ Influx-Mediated Damage and Regeneration of the Adult Myocardium

Ca^2 流入介导的成体心肌损伤和再生

• 批准号: 7488123
• 负责人: Steven R Houser
• 金额: $ 36.67万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7488123
• 关键词: Adrenergic Agents; Adrenergic Antagonists; Adrenergic Receptor; Adult; Age; Animals; Apoptosis; Biological Models; Blood; Blood Pressure; Cardiac; Cardiac Death; Cardiac Myocytes; Cardiovascular Diseases; Catecholamines; Cause of Death; Cell Death; Cessation of life; Congestive; Congestive Heart Failure; Data; Depressed mood; Disease; Doxycycline; Functional disorder; Generations; Growth; Heart; Heart Atrium; Heart Hypertrophy; Heart failure; Hypertension; Individual; Infusion procedures; Injury; Mediating; Metabolic; Metoprolol; Mus; Muscle Cells; Myocardial Infarction; Myocardial Ischemia; Myocardium; Natural regeneration; Necrosis; Numbers; P-2; Pathway interactions; Patients; Performance; Physiological; Precipitating Factors; Process; Propranolol; Proteins; Pump; Rate; Receptor Signaling; Recovery; Research; Role; Signal Pathway; Source; Stem cells; Stress; Sympathetic Nervous System; Syndrome; Testing; Thinking; Transgenic Mice; Transgenic Organisms; Ventricular; Work; adrenergic; concept; improved; mouse model; novel; prevent; programs; receptor; repaired; stem; theories

Cardiovascular disease culminates in a syndrome, congestive heart failure (CHF), in which the heart in unable to pump a sufficient quantity of blood to meet the metabolic needs of the individual. The factors that precipitate CHF and drive its progression are the topics of this research program. The proposed research challenges the existing dogmas that the initiation and progression of CHF is caused by weakening of myocyte contractility and that the adult heart is incapable of generating new myocytes. The working hypothesis of this research program is that a progressive reduction in the number of ventricular myocytes, rather than abnormalities in myocyte function, is the primary factor that initiates and causes progression of heart failure. Specific hypotheses are that myocyte death is induced by persistent increases in myocyte Ca2+ and that myocyte death can be offset by new myocyte formation, to slow or reverse CHF progression. To test these ideas we have generated a transgenic mouse with cardiac specific, inducible expression of a subunit (CaV1.2p2a) of the L-type Ca2+ channel, the major Ca2+ influx pathway in cardiac myocytes. Activation of CaV1.2(32a expression leads to increased myocyte Ca2+ influx, Ca2+ transients and contractility which initially culminates in increased ventricular performance. However, after a few months these mice have increased myocyte death, cardiac hypertrophy, ventricular and atrial dilation and reduced cardiac pump function. Interestingly, myocytes still have increased contractility. Preliminary studies also show that activation of the adrenergic signaling pathways, which also increase myocyte contractility, is involved in the initiation and progression of cardiac dysfunction in CaV1.2p2a mice. We have also recently shown that the normal heart has the capacity to generate new myocyte during periods of physiological and pathological growth. The specific aims of the proposed studies are 1) To determine if persistent increases in Ca2+ influx through the L-type Ca2+ channel induces CHF by causing increased myocyte death (via apoptosis and necrosis); 2) To determine if increased myocyte death induces an increase in new myocyte formation which slows the rate of myocyte loss and provides a mechanism for cardiac regeneration if the factors causing myocyte death (CaV1.2p2a expression) are eliminated; and 3) To determine if activation of Pradrenergic receptors in CaV1.2(32a mice exacerbates myocyte death and if activation of p2- adrenergic receptors blunts myocyte death and enhances new myocyte formation. We will also explore the role of myocyte death and new myocyte formation in the other models systems to be studied within this PPG. Support for our hypotheses will identify novel targets for CHF therapy and will change the thinking from current approaches that seek to increase myocyte force generation to those that seek to reduce myocyte death and promote myocyte regeneration.

心血管疾病的高潮是一种综合征，充血性心力衰竭（CHF），其中心脏无法 以泵送足够量的血液来满足个体的代谢需要。促成这一现象的因素 CHF及其发展是本研究项目的主题。拟议的研究挑战了 现有的教条认为CHF的开始和进展是由肌细胞收缩性减弱引起的， 成年人的心脏无法产生新的心肌细胞这个研究项目的工作假设 是心室肌细胞数量的逐渐减少，而不是心肌细胞的异常， 功能，是引发和导致心力衰竭进展的主要因素。具体假设有 肌细胞死亡是由肌细胞Ca 2+持续增加引起的， 新的肌细胞形成，以减缓或逆转CHF进展。为了测试这些想法，我们生成了一个 具有心脏特异性、可诱导表达L型Ca 2+亚基（CaV1.2p2a）的转基因小鼠 通道，心肌细胞中主要的Ca 2+内流途径。CaV1.2 β 2 α表达的激活导致 增加的肌细胞Ca 2+内流、Ca 2+瞬变和收缩力，其最初在增加的 心室性能然而，几个月后，这些小鼠的心肌细胞死亡增加，心脏 肥大、心室和心房扩张以及心脏泵功能降低。有趣的是，肌细胞仍然有 增强收缩力。初步研究还表明，肾上腺素能信号通路的激活， 也增加心肌细胞收缩力，参与心脏功能障碍的发生和发展。 CaV1.2p2a小鼠。我们最近还表明，正常的心脏有能力产生新的 在生理和病理生长期间的肌细胞。拟议研究的具体目标是 1)为了确定通过L型Ca 2+通道的Ca 2+内流的持续增加是否通过引起CHF而诱导CHF， 增加的肌细胞死亡（通过凋亡和坏死）; 2）为了确定增加的肌细胞死亡是否诱导了心肌细胞凋亡， 新的肌细胞形成增加，这减缓了肌细胞损失的速度，并提供了心脏 如果导致肌细胞死亡的因素（CaV1.2p2a表达）被消除，则再生;以及3）确定 如果CaV1.2 β 2 α小鼠中Pradrenergic受体的激活加剧了肌细胞死亡， 肾上腺素能受体减弱肌细胞死亡并增强新肌细胞形成。我们还将探讨 肌细胞死亡和新的肌细胞形成的其他模型系统内进行研究，在这个PPG。 支持我们的假设将确定CHF治疗的新靶点，并将改变目前的思维方式。 从寻求增加肌细胞力产生的方法到寻求减少肌细胞死亡和 促进肌细胞再生。