CORONARY TO MYOCYTE SIGNALING

描述：（申请人提供） 在上一个供资期间，我们集中研究了以下假设： 冠状循环产生的NO的消失是重要的， 心脏代偿失调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， 快速心室起搏导致心脏失代偿的时间。在 此外，我们还发现，NO生成的减少与 底物摄取从脂肪酸转移到葡萄糖， 体外耗氧量。我们以前的研究表明， 在起搏诱导的心力衰竭过程中，NO产生的减少是由于 ecNOS的mRNA和蛋白质减少。最近的研究表明， 他汀类药物通过作用于Rho增加NO合酶的信息半衰期 激酶，并且其不依赖于脂质降低。我们将使用他汀类药物， 起搏致心力衰竭时维持NOS蛋白、NO 并可能改变心力衰竭的进展， 具体目标1。在人类心脏中，我们最近发现， 左心室辅助装置（LVAD，卸载LV）的结果是 更大的生产，也许是生产的恢复，在时间的NO 然后移植到其他人的心脏里。具体目标2 确定NO生产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。的 心脏发育后停止快速心室起搏 衰竭导致心脏功能随时间至少部分恢复， NO的潜在作用以前没有被研究过。在具体目标3中， 我们将继续研究人类心脏的能力， 产生并回应NO.我们将专注于内心的差异 并检查cAMP作为增加NO产生的方法的作用 作为补偿机制。最后，在具体目标4中，我们将使用小鼠 缺乏产生NO的能力，ecNOS-/-小鼠，以确定 遗传性NO缺乏对血液动力学，心脏结构， 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，2）在 从起搏引起的心力衰竭中恢复。我们将使用人类的心脏， 4)转基因小鼠，以建立相关性和确定分子机制。

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.