Coronary to Myocyte Signaling

冠状动脉至心肌细胞信号传导

基本信息

批准号：
7252867
负责人：
Thomas H HINTZE
金额：
$ 43.64万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7252867
关键词：
Acute Address Aging Aldosterone Amphibia Angiotensin I Angiotensin II Angiotensins Animals Ascorbic Acid Biological Blood Plasma Volume Blood Volume Blood flow Canis familiaris Cardiac Chronic Conscious Coronary Coronary Circulation Dietary Sodium Disease Diuretics Enzymes Event Excretory function Exercise Fatty Acids Fishes Functional disorder Gene Expression Generations Genes Heart Heart failure Homeostasis Hyperhomocysteinemia Hypertension In Vitro Infusion procedures Intake Investigation Knockout Mice Lead Light Link Losartan Lucigenin Measures Metabolic Mus Muscle Cells NADPH Oxidase Nitric Oxide Numbers Output Oxidants Oxygen Consumption Patients Personal Satisfaction Physiological Plasma Pregnancy Process Production Publishing Radioactive Rattus Receptor, Angiotensin, Type 1 Regulation Renal function Renin Role Signal Transduction Sodium Sodium Chloride Sodium-Restricted Diet Stress Superoxides Time Tissues Urine Vasodilation Water acetovanillone base dietary restriction feeding glucose uptake heart metabolism human AKAP13 protein hypertension treatment in vivo instrument mortality mouse p47 oxidation pressure receptor salt intake uptake

项目摘要

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.

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，因为长期输注血管紧张素 II 期间的部分高血压是超氧化物依赖性的。血管紧张素II的高血压至少部分归因于超氧化物清除一氧化氮。因此，超氧化物的产生与NO生物效应降低之间的联系已经确立。我们最近的研究表明，调节心脏代谢、耗氧量和底物摄取是一氧化氮的重要作用之一，这不仅对调节生理状态（如运动和怀孕）的心脏效率很重要，而且对调节心脏效率也很重要。在一氧化氮被超氧化物清除的疾病状态下，一氧化氮生物活性的降低可能会促进疾病进程。有趣的是，血管紧张素 II 的最初生物学作用之一是控制血容量，因为血管紧张素 II 促进钠重吸收尤其是在盐摄入量有限的州。因此，限制盐饮食的患者和实验动物的血浆血管紧张素 II 水平会增加。如果血浆血管紧张素 II 的升高会增加超氧化物的产生并使 NO 失活，并且如果低盐饮食期间血浆血管紧张素 II 水平升高，那么低盐饮食是否会导致迄今为止未描述的内皮功能障碍和心脏代谢的改变？因此，我们假设低盐饮食会导致内皮功能障碍，其特征是心脏代谢和冠状动脉血流调节改变，随后血管紧张素 II 和超氧化物依赖性 NO 生物活性降低。在具体目标 1 中，我们将使用大鼠来确定肾功能、血浆血管紧张素 II、心脏代谢的变化以及低盐摄入期间 NADPH 氧化酶的作用。目标 2 将使用 gp91phox KO -/- 和 p47 -/- 小鼠心脏来进一步阐明血管紧张素II、NADPH氧化酶和NO在心脏代谢控制中的关系。我们将使用长期监测的有意识的狗来确定在限制盐摄入减少NO生物活性期间心脏代谢（具体目标3）以及心脏底物氧化和代谢基因表达（具体目标4）改变的时间过程和生物学基础。我们将研究使用利尿剂导致急性盐消耗引起的潜在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，即。事件与盐摄入量成反比。几乎与直觉相反的是，当盐摄入量增加时，低盐饮食的患者心脏事件似乎会减少。因此，我们的研究将探讨限制盐摄入量与内皮功能障碍之间的关系，特别是由于 NADPH 氧化酶产生超氧化物而改变 NO 生物活性的作用。