Mechanisms of ACE2 Regulation in Neurogenic Hypertension

ACE2在神经源性高血压中的调节机制

• 批准号: 8772578
• 负责人: ERIC D LAZARTIGUES
• 金额: $ 37.58万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8772578
• 关键词: Active Sites; Address; Affect; Aldosterone; American; Angiotensin II; Binding; Biological Markers; Blood Pressure; Blood Vessels; Blood specimen; Brain; Cardiology; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Culture Techniques; Cell membrane; Cells; Cessation of life; Cleaved cell; Clinical; Collaborations; DOCA; Data; Development; Diagnostic; Disintegrins; Down-Regulation; Enzymes; Event; Experimental Models; Genetic Models; Glutamates; High Prevalence; Human; Hypertension; Hypothalamic structure; Impairment; In Vitro; Individual; Inflammation; Knowledge; Lead; Maintenance; Mediating; Medical; Membrane; Metalloproteases; Modeling; Molecular; Mus; Myocardial Infarction; Neurons; Oxidative Stress; Patients; Peptides; Peptidyl-Dipeptidase A; Physiological; Plasma; Prevalence; Process; Property; Public Health; Regulation; Renal function; Renin-Angiotensin System; Reporting; Risk Factors; Signal Pathway; Signal Transduction; Sodium Chloride; Stimulus; Stroke; System; Testing; Therapeutic; Transgenic Organisms; United States; Vasodilator Agents; Vasopressins; Water; angiotensin I (1-7); clinically relevant; enzyme activity; hypertension treatment; improved; in vivo; neurogenic hypertension; normotensive; novel; overexpression; prevent; public health relevance; receptor; vasoconstriction

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.

描述（由申请人提供）：心血管疾病（CVD）是第一大死因，预计仍将是首要死因。在 CVD 中，全球高血压或高血压 (BP) 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单一危险因素，也是 2008 年 348,000 名美国人死亡的主要原因或促成原因，即每天有近 1,000 人死亡。在美国，高血压的患病率超过 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，大脑肾素-血管紧张素系统（RAS）在维持正常血压以及导致高血压的神经心血管失调中发挥着重要作用。血管紧张素 (Ang)-II 通过其 1 型受体 (AT1R) 促进交感神经活性增加，包括谷氨酸能活性增强、盐和水重吸收、血管收缩、醛固酮和加压素释放以及炎症，所有这些都会导致高血压。 ACE2（血管紧张素转换酶 2 型）将 Ang-II 裂解为血管舒张肽血管紧张素-(1-7) (Ang-(1-7))，并已被确定为 RAS ACE2/Ang-(1-7)/Mas 受体补偿轴的关键参与者。虽然大量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，但我们小组是第一个发现高血压中内源性脑 ACE2 翻译后损伤的研究小组。 ACE2 脱落是 ACE2 胞外域从质膜上裂解并分泌到周围环境的过程，是这些翻译后机制之一。我们的初步数据表明，ADAM17（一种解整合素和金属蛋白酶）介导 ACE2 脱落，从而导致高血压发展过程中细胞膜酶活性的丧失。该提议的中心假设是 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) 确定在高血压中保留 ACE2 代偿活性的治疗方法； 3) 解决分泌型 ACE2 (sACE2) 在人类高血压中的临床相关性。为了检验我们的假设，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，结合新颖独特的遗传模型，选择性删除前交感神经元中的 ADAM17，并在神经源性高血压 DOCA-盐模型中进行心血管分析。