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

心血管疾病最终导致一种综合征，即充血性心力衰竭(CHF)，在这种综合征中，心脏无法 泵出足够量的血液以满足个体的新陈代谢需求。催生的因素 CHF及其进展是本研究计划的主题。拟议的研究挑战了 现有的学说认为CHF的发生和发展是由心肌细胞收缩能力减弱和 成人心脏不能产生新的心肌细胞。这项研究计划的工作假设 这是心肌细胞数量的进行性减少，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。具体的假设是 心肌细胞死亡是由心肌细胞内钙离子持续增加引起的，而心肌细胞死亡可以通过 新的心肌细胞形成，以减缓或逆转心力衰竭的进展。为了测试这些想法，我们生成了一个 心脏特异、可诱导表达L型钙离子亚单位(CaV1.2p2a)的转基因小鼠 通道是心肌细胞内钙内流的主要途径。激活CaV1.2(32a表达导致 心肌细胞钙离子内流、钙瞬变和收缩能力增加，最初最终导致增加 脑室功能。然而，几个月后，这些小鼠增加了心肌细胞的死亡，心脏 心脏肥厚、心室和心房扩张，心泵功能减退。有趣的是，心肌细胞仍然有 可伸缩性增强。初步研究还表明，肾上腺素能信号通路的激活， 它还增加心肌细胞的收缩能力，参与心功能不全的发生和发展。 CaV1.2p2a小鼠。我们最近还表明，正常的心脏有能力产生新的 生理性和病理性生长期的肌细胞。拟议研究的具体目标是 1)确定通过L型钙离子通道持续增加的钙离子内流是否通过引起 增加心肌细胞死亡(通过凋亡和坏死)；2)确定增加的心肌细胞死亡是否导致 增加新的心肌细胞形成，减缓心肌细胞丢失的速度，并为心脏疾病提供一种机制 如果导致心肌细胞死亡的因素(CaV1.2p2a表达)被消除，则再生；以及3)确定 如果激活CaV1.2(32a小鼠)中的普拉达能受体会加剧心肌细胞的死亡，如果激活p2- 肾上腺素能受体抑制心肌细胞死亡，促进新的心肌细胞形成。我们还将探索其角色 在该PPG内研究的其他模型系统中的心肌细胞死亡和新的心肌细胞形成。 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 寻求增加肌细胞力量生成的方法与寻求减少心肌细胞死亡和 促进心肌细胞再生。

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.