High Salt Diet, Angiotensin II, and Microvessel Dilation

高盐饮食、血管紧张素 II 和微血管扩张

• 批准号: 8903552
• 负责人: JULIAN H LOMBARD
• 金额: $ 38.25万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8903552
• 关键词: Alleles; Angiotensin II; Animal Feed; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Area; Arteries; Ascorbic Acid; Attention; Binding; Blood Circulation; Blood Pressure; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular system; Cell Nucleus; Cells; Cessation of life; Chronic; Clinical Trials; Defense Mechanisms; Development; Diet; Dose; Down-Regulation; Enzymes; Epidermal Growth Factor Receptor; Equilibrium; Erythroid; Event; Exhibits; Exposure to; Future; Genes; Genetic Models; Goals; Health; Health Policy; Hormones; Human; Hypertension; Individual; Infusion procedures; Investigation; Knock-out; Knowledge; Lead; Maintenance; Mediating; Mitogen-Activated Protein Kinase 3; Nitric Oxide; Nuclear; Oxidants; Pathway interactions; Physiological; Plasma; Prognostic Marker; Property; Proteins; Public Health; Rattus; Regulation; Relaxation; Renin; Research; Resistance; Risk Factors; Role; Sodium Chloride; Sprague-Dawley Rats; Survivors; System; Testing; Therapeutic; Transactivation; Up-Regulation; Vascular Diseases; Vasodilator Agents; body system; cerebral artery; congenic; endothelial dysfunction; feeding; genetic regulatory protein; human disease; innovation; insight; interest; knockout gene; mortality; normotensive; novel; oxidant stress; pressure; prevent; protective effect; receptor; response; salt intake; transcription factor; vascular bed; volunteer

DESCRIPTION (provided by applicant): High salt (HS) diet leads to endothelial dysfunction, impaired vascular relaxation and increased oxidant stress in blood vessels. Salt-induced angiotensin II (ANG II) suppression is a crucial factor contributing to this vascular dysfunction. Normal vascular function can be restored in HS-fed animals by chronic i.v. infusion of a subpressor dose of ANG II to prevent salt-induced ANG II suppression. This protective action of ANG II is mediated via transactivation of the EGF receptor and subsequent activation of the ERK 1/2 pathway. The goal of this project is to elucidate the mechanisms by which ANG II maintains normal vascular relaxation via this pathway, with special emphasis on the role of ANG II in maintaining antioxidant defense mechanisms. The fundamental hypothesis of this project is that physiological levels of ANG II in the plasma are required to maintain normal endothelial function and to preserve anti-oxidant defense mechanisms by tonic activation of the AT1 receptor, which transactivates the epidermal growth factor (EGF) receptor leading to activation of the ERK 1/2 pathway and ultimately, activation of the master antioxidant and cytoprotective transcription factor Nrf2 [also known as nuclear factor (erythroid derived 2)-like 2]. We further hypothesize that the severe endothelial dysfunction that exists with high salt diet results from chronic exposure to low levels of ANG II due to salt-induced suppression of plasma renin activity--the normal physiological response to elevated dietary salt intake. These low levels of ANG II, in turn, lead to down regulation of antioxidant genes in resistance arteries by suppressing the Nrf2 pathway. This project has three specific aims: 1): To directly evaluate the role of reduced plasma ANG II levels in contributing to vascular oxidant stress and endothelial dysfunction utilizing congenic knockout rats with and without a normally functioning renin allele; 2) To evaluate the role of the Nrf2 pathway in mediating the protective effect of physiological ANG II levels to prevent vascular oxidant stress and endothelial dysfunction in cerebral arteries. 3) To evaluate the role of physiological ANG II levels and the Nrf2 pathway in maintaining normal blood flow regulation at the level of the whole vascular bed. These studies could open entirely new areas of investigation related to a previously unknown role of physiological levels of ANG II, namely the maintenance of antioxidant defense mechanisms and normal vascular relaxation in resistance arteries via the Nrf2 pathway.

描述（由申请人提供）：高盐饮食导致血管内皮功能障碍、血管松弛受损和血管氧化应激增加。盐诱导的血管紧张素II （ANG II）抑制是导致这种血管功能障碍的关键因素。通过长期静脉输注一定剂量的ANG II亚压剂，可以恢复hs喂养动物的正常血管功能，以防止盐诱导的ANG II抑制。ANG II的这种保护作用是通过EGF受体的反激活和随后的ERK 1/2通路的激活来介导的。该项目的目的是阐明ANG II通过这一途径维持正常血管松弛的机制，特别强调ANG II在维持抗氧化防御机制中的作用。本项目的基本假设是，血浆中生理水平的ANG II需要维持正常的内皮功能，并通过强直激活AT1受体来维持抗氧化防御机制，AT1受体会激活表皮生长因子（EGF）受体，从而激活ERK 1/2通路，最终，激活主抗氧化和细胞保护转录因子Nrf2[也称为核因子（红细胞衍生2）样2]。我们进一步假设，高盐饮食中存在的严重内皮功能障碍是由于长期暴露于低水平的ANG II，这是由于盐诱导的血浆肾素活性抑制——这是对高盐饮食摄入量的正常生理反应。反过来，这些低水平的ANG II通过抑制Nrf2途径导致抵抗动脉中抗氧化基因的下调。该项目有三个具体目标：1)：利用具有和不具有正常功能肾素等位基因的基因敲除大鼠，直接评估血浆ANG II水平降低在血管氧化应激和内皮功能障碍中的作用；2)评价Nrf2通路介导生理性ANG II水平对预防脑动脉血管氧化应激和内皮功能障碍的保护作用。3)在全血管床水平上评价生理性ANG II水平和Nrf2通路在维持正常血流调节中的作用。这些研究可以打开一个全新的研究领域，与以前未知的生理水平的作用有关