Coronary to Myocyte Signaling

冠状动脉至心肌细胞信号传导

• 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
• 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; 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

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型1受体的激活，超氧化物的产生增加，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的生物学作用，因为在慢性血管紧张素II输注过程中的一部分高血压是超氧化物依赖性的。血管紧张素II的高血压至少部分是由于超氧化物清除一氧化氮。因此，已经建立了超氧化物的产生与NO生物学作用的减少之间的联系。我们最近的研究表明，对心脏代谢，氧气消耗和底物的摄取的调节是NO的重要作用之一，这不仅在调节生理状态的心脏效率方面可能很重要，例如运动和妊娠，而且在疾病中，在疾病中，在疾病中没有被超氧疾病的生物活性所造成的生物活性。有趣的是，血管紧张素II的最初生物学作用之一是对血容量的控制，因为血管紧张素II促进了钠的重吸收 尤其是在盐分摄入量有限的状态下。因此，血浆血管紧张素II的水平在受盐限制饮食中的患者和实验动物的水平增加。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，并且血浆血管紧张素II水平在低盐饮食期间增加，那么低盐饮食会导致迄今未描述的内皮功能障碍并导致心脏代谢的改变？因此，我们假设低盐饮食会导致内皮功能障碍，其特征是心脏代谢改变和冠状动脉流动调节，此后降低了无生物活性II和超氧化物依赖性的生物活性。在特定目标1中，我们将使用大鼠确定肾功能，血浆血管紧张素II，心脏代谢以及NADPH氧化酶在低盐摄入量中的作用。 AIM 2将使用GP91Phox KO - / - 和P47 - / - 鼠标心脏进一步阐明 血管紧张素II，NADPH氧化酶与心脏代谢的控制之间的关系。我们将使用慢性仪器有意识的狗来确定心脏代谢，特定AIM3以及心脏底物氧化和代谢基因表达的时间过程和生物学基础，在限制盐摄入量减少的过程中，没有生物活性。我们将检查由于使用利尿剂而导致的潜在内皮功能障碍的机理。有趣的是，与正常盐摄入量相比，低盐饮食的患者的心脏事件可能会增加。事件与盐摄入量成反比。几乎与直觉上的相反，低盐饮食的患者在增加盐的摄入量时会减少心脏事件。因此，我们的研究将研究限制性盐摄入量和内皮功能障碍之间的关系，并特别提及NADPH氧化酶产生超氧化物引起的无生物活性的作用。