CORONARY TO MYOCYTE SIGNALING

描述：（由申请人提供）

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.