High Salt Diet, Angiotensin II, and Microvessel Dilation

描述（由申请人提供）：在没有血压升高的情况下，高盐（HS）饮食会导致血管松弛机制的严重和广泛的损害，以及调节组织灌注的能力受损。HS饮食对血管紧张素II （ANG II）的抑制是导致血管松弛受损的一个关键因素，因为这种影响可以通过长期静脉注射抑制剂量的ANG II来防止盐诱导的血浆ANG II的抑制。一个意想不到的发现是，喂食HS饮食的大鼠血管松弛受损伴随着氧化应激水平的增加，这也可以通过ANG II输注来预防。ANG II的这种作用似乎是通过EGF受体的反激活介导的，因为它可以通过输注EGF来模拟，并且在HS饮食的动物中，ANG II和EGF恢复血管松弛的保护作用可以通过抑制EGF受体或ERK 1/2途径来阻止。这项更新应用的目的是阐明ANG II恢复HS饮食大鼠血管松弛的机制（特别强调EGF受体反激活和ERK 1/2通路在维持血管松弛和正常抗氧化防御机制中的作用）。我们的基本假设是，HS饮食的大鼠血管松弛受损是由于铜/锌超氧化物歧化酶（Cu/Zn SOD）等抗氧化酶的下调和促氧化酶的上调导致血管氧化应激的增加。我们进一步假设ANG II通过反激活EGF受体发挥其保护作用，维持正常血管舒张，导致抗氧化酶（如Cu/Zn SOD）的表达增加。该项目的具体目的是：1)评估ANG II和EGF受体的反激活在通过ERK 1/2通路预防氧化应激和维持正常血管舒张机制中的作用；2)评估ANG II和EGF受体反激活通过ERK 1/2通路调节促氧化酶和抗氧化酶表达的作用；3)评价LS和HS日粮大鼠血管中促氧化酶和抗氧化酶活性，并确定恢复血浆ANG II水平对这些酶活性的影响。本应用程序中提出的研究可以为理解ANG II的生理作用开辟一个全新的领域，即通过防止抵抗动脉氧化应激来维持正常的血管松弛。公共卫生相关性：越来越多的证据表明，膳食盐摄入量的增加会导致血管功能的显著改变，而不会导致血压升高。在喂食高盐饮食的大鼠和其他物种中发生的许多血管变化使人想起高血压、动脉粥样硬化和高胆固醇血症等血管疾病的病理改变。高盐饮食对血管功能的损害似乎是由血管氧化应激的增加和血管紧张素II （ANG II）的抑制介导的。本项目将验证ANG II抑制通过下调血管抗氧化防御机制直接导致氧化应激增加的假设。这些研究应该为高盐饮食在盐敏感性高血压患者血压升高之前发生的早期变化以及高盐饮食摄入引起的病理变化提供有价值的见解。

DESCRIPTION (provided by applicant): High salt (HS) diet leads to a dramatic and widespread impairment of vascular relaxation mechanisms and an impaired ability to regulate tissue perfusion in the absence of an elevated blood pressure. Angiotensin II (ANG II) suppression in response to HS diet is a crucial factor contributing to impaired vascular relaxation, since this effect can be prevented by chronic i.v. infusion of a subpressor dose of ANG II to prevent salt-induced suppression of plasma ANG II. An unexpected finding is that impaired vascular relaxation in rats fed HS diet is accompanied by an increased level of oxidative stress that can also be prevented by ANG II infusion. This action of ANG II appears to be mediated via transactivation of the EGF receptor, because it can be mimicked by infusion of EGF, and the protective effect of both ANG II and EGF to restore vascular relaxation in animals on HS diet can be prevented by inhibiting the EGF receptor or the ERK 1/2 pathway. The goal of this renewal application is to elucidate the mechanisms by which ANG II restores vascular relaxation in rats fed HS diet (with special emphasis on the role of EGF receptor transactivation and the ERK 1/2 pathway in maintaining vascular relaxation and normal antioxidant defense mechanisms). Our fundamental hypothesis is that impaired vascular relaxation in rats fed HS diet is due to an increase in vascular oxidative stress resulting from down regulation of antioxidant enzymes such as copper/zinc superoxide dismutase (Cu/Zn SOD), and possibly upregulation of pro- oxidant enzymes. We further hypothesize that ANG II exerts its protective effect to maintain normal vascular relaxation via transactivation of the EGF receptor, leading to increased expression of antioxidant enzymes, e.g., Cu/Zn SOD. The Specific Aims of this project are to: 1) evaluate the role of ANG II and EGF receptor transactivation in preventing oxidative stress and maintaining normal vascular relaxation mechanisms via the ERK 1/2 pathway; 2), evaluate the role of ANG II and EGF receptor transactivation in regulating the expression of pro- and antioxidant enzymes via the ERK 1/2 pathway; and 3) evaluate pro- and anti-oxidant enzyme activity in vessels from rats fed LS and HS diet, and to determine the effect of restoring plasma ANG II levels on the activities of these enzymes. The studies proposed in this application could open an entirely new area in the understanding of the physiological roles of ANG II, namely the maintenance of normal vascular relaxation by preventing oxidative stress in resistance arteries. PUBLIC HEALTH RELEVANCE: A growing body of evidence indicates that elevated dietary salt intake leads to dramatic alterations in vascular function without an increase in blood pressure. Many of the vascular changes occurring in rats and other species fed high salt diet are reminiscent of pathological alterations seen in vascular diseases such as hypertension, atherosclerosis, and hypercholesterolemia. Impaired vascular function with high salt diet appears to be mediated by increased oxidative stress in the blood vessels and suppression of the hormone angiotensin II (ANG II). This project will test the hypothesis that ANG II suppression leads directly to increased oxidative stress via down-regulation of antioxidant defense mechanisms in the blood vessels. These studies should provide valuable insight into the early changes occurring in response to high salt diet prior to elevation of blood pressure in salt sensitive hypertension, as well as the pathological changes that occur in response to elevated dietary salt intake.