CORONARY TO MYOCYTE SIGNALING

冠状动脉至心肌细胞信号传导

• 批准号: 6931015
• 负责人: Thomas H HINTZE
• 金额: $ 30.26万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6931015
• 关键词: blood flow measurement; cardiac myocytes; cardiovascular pharmacology; cellular respiration; coronary vessels; dogs; enzyme activity; glucose metabolism; heart circulation; heart failure; heart function; heart prosthesis; hemodynamics; laboratory mouse; microcirculation; myocardium disorder; nitric oxide; nitric oxide synthase; oxygen consumption; pathologic process; pharmacokinetics; vascular endothelium; vascular resistance; vasomotion

DESCRIPTION: (provided by applicant) During the previous funding period we have concentrated on the hypothesis that the disappearance of NO production by the coronary circulation is important in the process of cardiac decompensation. Those aims were supported by showing that the production of NO both in vivo and in vitro essentially disappears at the time of cardiac decompensation caused by rapid ventricular pacing. In addition, we showed that the reduction in NO production was associated with a shift in substrate uptake from fatty acids to glucose and to an increase in oxygen consumption in vitro. Our previous studies indicated that the reduction in NO production during pacing induced heart failure was due to a reduction in the mRNA and protein for ecNOS. Recently it has been shown that statins increase the message half-life for NO synthase by an action on Rho kinase and that is independent of lipid lowering. We will use statins during the evolution of pacing induced heart failure to maintain NOS protein, NO production and potentially to alter the progression of heart failure in Specific Aim 1. In the human heart we have recently found that implantation of an left ventricular assist device (LVAD, to unload the LV) results in a greater production, perhaps the recovery of production, of NO at the time of transplant then in other falling human hearts. In Specific Aim 2 we will determine if the regeneration of NO production contributes to the recovery of dilated myopathy and heart failure after cessation of pacing. The discontinuation of rapid ventricular pacing after the development of heart failure results in at least partial recovery of cardiac function over time and the potential role of NO has not been previously studied. In Specific Aim 3, we will continue to study the ability of the explanted falling human heart to produce and respond to NO. We will concentrate on the difference in hearts with LVAD and examine the role of cAMP as a method to increase NO production as a compensatory mechanism. Finally in specific Aim 4, we will use mice deficient in ability to produce NO, ecNOS-/- mice, to determine the consequence of the genetic lack of NO on hemodynamics, cardiac structure, function and glucose metabolism with time. Thus, we will establish new directions 1) examining the role of NO in the therapeutic and 2) in the recovery from pacing induced heart failure. We will use 3) human hearts and 4) transgenic mice to establish relevance and determine molecular mechanisms.

描述：（由申请人提供） 在之前的资助期间，我们集中研究了这样的假设： 冠状循环中 NO 产生的消失对于 心脏失代偿的过程。这些目标得到了支持 体内和体外NO的产生基本上消失 心室快速起搏引起心脏失代偿的时间。在 此外，我们发现 NO 产生的减少与 底物吸收从脂肪酸转向葡萄糖，并增加 体外耗氧量。我们之前的研究表明 起搏引起的心力衰竭期间 NO 产生的减少是由于 ecNOS 的 mRNA 和蛋白质减少。最近有研究表明 他汀类药物通过作用于 Rho 来延长 NO 合酶的信息半衰期 激酶并且与降脂无关。我们将在治疗期间使用他汀类药物 起搏诱导心力衰竭的进化维持NOS蛋白，NO 产生并可能改变心力衰竭的进展 具体目标 1. 我们最近在人类心脏中发现植入 左心室辅助装置（LVAD，以卸载 LV）会导致 更大的产量，也许是产量的恢复，在当时 然后移植到其他堕落的人类心脏中。在具体目标 2 中，我们将 确定 NO 产生的再生是否有助于恢复 停止起搏后扩张性肌病和心力衰竭。这 心脏发育后停止快速心室起搏 随着时间的推移，失败导致心功能至少部分恢复，并且 NO 的潜在作用此前尚未被研究过。在具体目标 3 中， 我们将继续研究摘除的坠落人类心脏的能力 产生并响应NO。我们将专注于内心的差异 与 LVAD 并检查 cAMP 作为增加 NO 产生的方法的作用 作为一种补偿机制。最后在具体目标 4 中，我们将使用小鼠 缺乏产生 NO 能力的 ecNOS-/- 小鼠，以确定 遗传性缺乏一氧化氮对血流动力学、心脏结构、 功能和葡萄糖代谢随时间的变化。因此，我们将建立新的 方向 1) 检查 NO 在治疗中的作用以及 2) 在 从起搏引起的心力衰竭中恢复。我们将使用 3) 人心和 4)建立转基因小鼠相关性并确定分子机制。