Coronary to Myocyte Signaling

最近的证据表明，由于血管紧张素II 1型受体的激活，超氧化物的产生增加，并且超氧化物来自NADPH氧化酶。这种超氧化物有助于血管紧张素II的生物效应，因为在慢性血管紧张素II输注过程中，高血压的一部分是依赖于超氧化物的。血管紧张素II的高血压至少部分是由于超氧化物对一氧化氮的清除。因此，超氧化物的产生和NO生物效应的减少之间的联系已经建立起来。我们最近的研究表明，心脏代谢、氧耗和底物摄取的调节是NO的重要作用之一，这不仅在运动和怀孕等生理状态下调节心脏效率可能是重要的，而且在NO被超氧化物清除的疾病状态下，NO生物活性的降低可能有助于疾病的进程。有趣的是，血管紧张素II最初的生物学作用之一是控制血容量，因为血管紧张素II促进钠的重吸收。 尤其是在盐摄入量有限的州。因此，在盐限制饮食的患者和实验动物中，血浆血管紧张素II水平增加。如果血浆血管紧张素II的升高增加了超氧化物的产生和NO的失活，如果在低盐饮食期间血浆血管紧张素II水平增加，那么低盐饮食是否会导致迄今未被描述的内皮功能障碍和心脏代谢的改变？因此，我们假设低盐饮食导致内皮功能障碍，其特征是心脏代谢和冠脉血流调节改变，随后NO生物活性降低，这是血管紧张素II和超氧化物依赖的。在具体目标1中，我们将使用大鼠来确定低盐摄入时肾功能、血浆血管紧张素II、心脏代谢和NADPH氧化酶的作用。Aim 2将使用gp91Phox KO-/-和p47-/-小鼠心脏进一步阐明 血管紧张素II、NADPH氧化酶与NO在心脏代谢调控中的关系我们将使用慢性仪器化清醒的狗来确定在限制盐摄入以减少NO生物活性的过程中，心脏代谢改变的时间进程和生物学基础，特定的AIM 3，以及心脏底物氧化和代谢基因的表达，特定的目标4。我们将使用利尿剂研究急性盐耗所致潜在的内皮功能障碍的机制。有趣的是，与正常盐摄入量的患者相比，低盐饮食的患者心脏事件可能会增加。这些事件与盐的摄入量成反比。几乎与直觉相反的是，当盐的摄入量增加时，低盐饮食的患者心脏事件似乎减少了。因此，我们的研究将考察盐摄入量限制和内皮功能障碍之间的关系，特别是NADPH氧化酶产生的超氧化物导致的NO生物活性改变的作用。

Recent evidence suggests that there is an increase in superoxide production due to activation of the angiotensin II type 1 receptor and that the superoxide comes from the NADPH oxidase. This superoxide contributes to the biological effects of angiotensin II in that a portion of the hypertension during chronic angiotensin II infusion is superoxide dependent. The hypertension to angiotensin II is at least in part due to the scavenging of nitric oxide by superoxide. Thus, the link between the generation of superoxide and the reduction in the biological effects of NO has already been established. Our recent studies suggest that the regulation of cardiac metabolism, oxygen consumption and substrate uptake, is one of the important actions of NO and that this may not only be important in the regulation of cardiac efficiency in physiologic states, such as exercise and pregnancy, but that in disease states where NO is scavenged by superoxide, the decreased bioactivity of NO may contribute to the disease process. Interestingly, one of the initial biologic actions of angiotensin II was the control of blood volume, since angiotensin II promotes sodium reabsorption especially in states where salt intake is limited. Thus plasma angiotensin II levels increase in patients and experimental animals on a salt restricted diet. If a rise in plasma angiotensin II increases superoxide production and inactivates NO, and if plasma angiotensin II levels increase during low salt diet, then does a low salt diet result in a hitherto undescribed endothelial dysfunction and to alterations in cardiac metabolism? Thus we hypothesize that low salt diet results in endothelial dysfunction characterized by altered cardiac metabolism and coronary blood flow regulation subsequent to reduced NO bioactivity that is angiotensin II and superoxide dependent. In specific aim 1 we will use rats to determine changes in renal function, plasma angiotensin II, cardiac metabolism and the role of the NADPH oxidase during low salt intake. Aim 2 will use the gp91phox KO -/- and p47 -/- mouse heart to further elucidate the relationship between angiotensin II, the NADPH oxidase and NO in the control of cardiac metabolism. We will use chronically instrumented conscious dogs to determine the time course and biological basis for alterations in cardiac metabolism, specific aim3, and in cardiac substrate oxidation and metabolic gene expression, specific aim 4, during restricted salt intake reduction in NO bioactivity. We will examine the mechanism of potential endothelial dysfunction due to acute salt depletion using a diuretic. Interestingly, patients on a low salt diet may have an increase in cardiac events compared to those on normal salt intake, ie. events are inversely proportional to salt intake. Almost counter intuitively, it seems that patients on a low salt diet have a reduction in cardiac events when salt intake is increased. Thus our studies will examine the relationship between restricted salt intake and endothelial dysfunction with special reference to the role of altered NO bioactivity due to superoxide generation by the NADPH oxidase.