Mechanisms of ACE2 Regulation in Neurogenic Hypertension

描述（由申请人提供）：心血管疾病（CVD）是头号死因，预计仍将是主要死因。在CVD中，高血压或高血压（BP）的全球患病率估计可能高达10亿人。高血压是中风和心脏病发作的最大危险因素，2008年是348，000名美国人死亡的主要或促成原因，或每天近1，000人死亡。在美国，高血压的患病率高于33%，高血压仍然是一个日益重要的医疗和公共卫生问题。有证据表明，脑内的肾素-血管紧张素系统（RAS）在维持正常血压和导致高血压的神经-心血管失调中的重要性。血管紧张素（Ang）-II通过其1型受体（AT 1 R）促进交感神经活性增加，包括增强的血管紧张素能活性、盐和水重吸收、血管收缩、醛固酮和加压素释放和炎症，所有这些都有助于高血压。ACE 2（血管紧张素转换酶2型）将Ang-Ⅱ切割成血管舒张肽血管紧张素-（1-7）（Ang-（1- 7）），并已被鉴定为RAS的ACE 2/Ang-（1-7）/Mas受体补偿轴中的关键参与者。虽然许多过表达研究已经确定了ACE 2在实验模型中预防高血压进展和改善高血压治疗方面的益处，但我们的小组是第一个显示高血压中内源性脑ACE 2的翻译后损伤的小组。ACE 2脱落是ACE 2胞外域从质膜裂解并分泌到周围环境中的过程，是这些翻译后机制之一。我们的初步数据表明，ADAM 17（一种去整合素和金属蛋白酶）介导ACE 2脱落，从而导致高血压发生过程中细胞膜酶活性的丧失。该建议的中心假设是Ang-II促进ACE 2脱落，导致RAS过度活性和神经源性高血压。靶向ADAM 17介导的脱落将恢复ACE 2的代偿特性并降低高血压。本申请的直接目的是：1）表征导致ACE 2脱落的信号传导途径; 2）确定在高血压中保持ACE 2代偿活性的治疗方法; 3）解决分泌型ACE 2（sACE 2）在人高血压中的临床相关性。为了验证我们的假设，我们将使用最先进的体外和体内分子，细胞，药理学和临床方法，结合新的和独特的遗传模型，在交感神经前神经元中选择性缺失ADAM 17，并在神经源性高血压的DOCA盐模型中进行心血管分析。

DESCRIPTION (provided by applicant): Cardiovascular diseases (CVD) are the number one cause of death and are projected to remain the leading cause of death. Among CVD, worldwide prevalence estimates for hypertension, or high blood pressure (BP), may be as much as 1 billion individuals. Hypertension is the single biggest risk factor for stroke and heart attacks, ad a primary or contributing cause of death for 348,000 Americans in 2008, or nearly 1,000 deaths a day. With prevalence higher than 33% in United States, hypertension remains an increasingly important medical and public health issue. Evidence has shown the importance of the brain renin-angiotensin system (RAS) in the maintenance of normal BP and in the neuro-cardiovascular dysregulation leading to hypertension. Angiotensin (Ang)-II, by means of its type 1 receptor (AT1R), promotes increased sympathetic activity, including enhanced glutamatergic activity, salt and water reabsorption, vasoconstriction, aldosterone and vasopressin release and inflammation, all contributing to high BP. ACE2 (angiotensin converting enzyme type 2) cleaves Ang- II into the vasodilator peptide angiotensin-(1-7) (Ang-(1-7)) and has been identified as a pivotal player in the ACE2/Ang-(1-7)/Mas receptor compensatory axis of the RAS. While numerous overexpression studies have established the benefits of ACE2 in preventing the progression and improving the treatment of hypertension in experimental models, our group our group was the first to show post- translational impairment of endogenous brain ACE2 in hypertension. ACE2 shedding, a process by which the ACE2 ectodomain is cleaved from the plasma membrane and secreted into the surrounding milieu, is one of these post-translational mechanisms. Our preliminary data suggest that ADAM17 (A Disintegrin And Metalloprotease) mediates ACE2 shedding, thus contributing to a loss in cell membrane enzyme activity during the development of hypertension. The central hypothesis of this proposal is that Ang-II promotes ACE2 shedding, leading to RAS over-activity and neurogenic hypertension. Targeting of ADAM17-mediated shedding will restore ACE2 compensatory properties and reduce hypertension. The immediate objectives of this application are: 1) to characterize the signaling pathways leading to ACE2 shedding; 2) to identify therapeutic approaches to preserve ACE2 compensatory activity in hypertension; and to 3) address the clinical relevance of secreted ACE2 (sACE2) in human hypertension. To test our hypothesis, we will use state-of-the-art in vitro and in vivo molecular, cellular, pharmacological and clinical approaches combined with novel and unique genetic models with selective deletion of ADAM17 in pre-sympathetic neurons and cardiovascular analysis in the DOCA-salt model of neurogenic hypertension.