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：（申请人提供） 在上一个资金期间，我们集中于以下假设 冠状动脉循环无生产的消失在 心脏代理的过程。这些目标得到了证明的支持 在 由于快速心室起搏引起的心脏代偿失调时间。在 此外，我们表明，没有生产的减少与 底物的摄取从脂肪酸转移到葡萄糖并增加 体外消耗氧。我们以前的研究表明 在起搏引起的心力衰竭期间无产生的降低是由于 MRNA和蛋白质的蛋白质减少。最近已经表明 他汀类药物通过对Rho的动作增加了无合酶的半衰期的消息 激酶，这与降低脂质无关。我们将在 起搏的演变引起的心力衰竭维持NOS蛋白，否 生产并有可能改变心力衰竭的进展 特定目的1。在人类心脏中，我们最近发现植入 左心室辅助装置（LVAD，卸载LV）导致 在没有的生产时，也许是生产的回收 然后在其他落下的人心中移植。在特定目标2中，我们将 确定没有生产的再生是否有助于恢复 停止起搏后，肌病和心力衰竭扩张。这 心脏发展后停止快速心室起搏 失败会导致至少部分恢复心脏功能，并且随着时间的流逝而 先前尚未研究NO的潜在作用。在特定的目标3中 我们将继续研究外opp灭的人类心脏的能力 生产并回应否。我们将专注于心脏的差异 使用LVAD并研究CAMP作为增加生产的方法的作用 作为补偿机制。最后，在特定目标4中，我们将使用小鼠 缺乏产生否，ecnos - / - 小鼠的能力，确定 遗传缺乏NO在血液动力学，心脏结构上的结果， 随时间的功能和葡萄糖代谢。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） 从起搏中恢复引起的心力衰竭。我们将使用3）人类的心和 4）转基因小鼠建立相关性并确定分子机制。