Mechanisms of ACE2 Regulation in Neurogenic Hypertension

描述（由申请人提供）：心血管疾病（CVD）是导致死亡的头号原因，预计仍将是导致死亡的主要原因。在心血管疾病中，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风险因素，也是2008年34.8万美国人死亡的主要原因或促成原因，相当于每天近1000人死亡。高血压在美国的患病率超过33%，是一个日益重要的医学和公共卫生问题。有证据表明，脑肾素-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（AT1R）促进交感神经活动的增加，包括增强谷氨酸能活性、盐和水的重吸收、血管收缩、醛固酮和加压素的释放和炎症，所有这些都导致血压升高。ACE2 （angiotensin converting enzyme type 2）将Ang- II裂解为血管舒张肽angiotensin-(1-7) (Ang-(1-7))，并被认为是RAS的ACE2/Ang-(1-7)/Mas受体代偿轴的关键参与者。虽然大量的过表达研究已经在实验模型中证实了ACE2在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在高血压中发现内源性脑ACE2翻译后损伤的小组。ACE2脱落是一种翻译后机制，即ACE2胞外结构域从质膜上断裂并分泌到周围环境中的过程。我们的初步数据表明，ADAM17 （A Disintegrin And Metalloprotease）介导ACE2脱落，从而在高血压的发展过程中导致细胞膜酶活性的丧失。该建议的中心假设是Ang-II促进ACE2脱落，导致RAS过度活跃和神经源性高血压。靶向adam17介导的脱落将恢复ACE2代偿特性并降低高血压。该应用的直接目标是：1)表征导致ACE2脱落的信号通路；2)确定维持高血压患者ACE2代偿活性的治疗方法；3)探讨人类高血压中分泌的ACE2 （sACE2）的临床意义。为了验证我们的假设，我们将采用最先进的体外和体内分子、细胞、药理学和临床方法，结合新颖独特的遗传模型，在前交感神经元中选择性缺失ADAM17，并在神经源性高血压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.