New strategies to restore ACE2 compensatory activity in neurogenic hypertension

恢复神经源性高血压中 ACE2 代偿活性的新策略

• 批准号: 10266017
• 负责人: ERIC D LAZARTIGUES
• 金额: --
• 依托单位: SOUTHEAST LOUISIANA VETERANS HEALTH CARE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266017
• 关键词: ACE2; APLN gene; Address; Affect; Age; Agonist; Aldosterone; Angiotensin II; Attenuated; Binding; Blood Pressure; Bradykinin; Brain; Cardiovascular Diseases; Cardiovascular system; Cleaved cell; Data; Development; Diabetes Mellitus; Disease; Down-Regulation; Enzymes; Experimental Models; Family; Future; G-Protein-Coupled Receptors; Genetic; Genetically Engineered Mouse; Habits; Healthcare Systems; High Prevalence; Hospitalization; Hypertension; Hypothalamic structure; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Investigation; Knock-out; Laboratories; Leupeptins; Life Style; Losartan; Lysine; Lysosomes; Maintenance; Mediating; Medical; Modeling; Molecular; Mutation; Neurons; Opioid Peptide; PPAR gamma; Pathway interactions; Peptides; Peptidyl-Dipeptidase A; Peroxisome Proliferator-Activated Receptors; Pharmacology; Play; Public Health; Renin-Angiotensin System; Reporting; Risk Factors; Role; Site; Smoking; Sodium Chloride; System; Telemetry; Testing; Therapeutic; Time; Transgenic Organisms; Ubiquitination; United States; United States Department of Veterans Affairs; Vasodilator Agents; Vasopressins; Veterans; Veterans Health Administration; Water; Work; angiotensin I (1-7); base; beta-arrestin; conditional knockout; design; disability; human old age (65+); hypertension treatment; improved; in vivo; inhibitor/antagonist; innovation; member; mortality; mouse model; neurogenic hypertension; novel; novel strategies; novel therapeutic intervention; optogenetics; overexpression; preservation; prevent; receptor; research and development; response; rosiglitazone; tool; treatment strategy; vasoconstriction

With prevalence higher than 33% in United States, hypertension is a major risk factor contributing to cardiovascular diseases (CVD) and global mortality, hence remaining an increasingly important medical and public health issue. According to the Veterans’ Affairs (VA) Office of Research & Development, CVD, including hypertension, are the number-one killer in the USA, the leading cause of hospitalization in the VA health care system and a major cause of disability. Recent studies have documented that hypertension occurs at a younger age than it used to, now affecting individuals of deployment age and future veterans. Hypertension is also important to Veterans because it affects 60 percent of people over age 65 and it is associated with a number of diseases, like diabetes, and lifestyle habits, like smoking, that contribute to its development. The role of the brain renin-angiotensin system (RAS) in the maintenance of normal blood pressure (BP) and in the neuro-cardiovascular dysregulation leading to hypertension has been firmly established. Angiotensin (Ang)-II, by means of its type 1 receptor (AT1R), promotes increased sympathetic activity, salt and water reabsorption, vasoconstriction, aldosterone and vasopressin release and inflammation, all contributing to hypertension. Angiotensin Converting Enzyme type 2 (ACE2), one of the latest identified members of this system plays a compensatory role to the activation of the RAS. Numerous studies have shown that ACE2 overexpression prevents experimental hypertension. However, our laboratory reported that Ang-II mediates ACE2 internalization and degradation via AT1R activation, effects that were prevented by pretreatment with leupeptin, a lysosomal inhibitor. The detailed mechanism leading to the loss of ACE2 compensatory activity has not been investigated. This proposal aims at targeting this new mechanism responsible for ACE2 down-regulation, originally described by our group, to design innovative strategies for the treatment of hypertension. The efficacy of these strategies will be evaluated by their ability to prevent ACE2 internalization and preserve ACE2 compensatory in the context of neurogenic hypertension. Our preliminary data, show that ubiquitination of the C-terminus of ACE2 is a major mechanism leading to ACE2 degradation. In addition, stimulation of the β-arrestin pathway with an AT1R-biased agonist increased ACE2 activity in neurons. Finally, ACE2 internalization may involve other members of the G-protein coupled receptor family (GPCR), like bradykinin B1 receptors (B1R) interacting with the RAS. Thus, the hypothesis of this work is that AT1R and B1R blunts ACE2 compensatory activity through multiple binding partners affecting its expression levels, subcellular localization and enzymatic activity. Pharmacological and genetic targeting of these binding partners may constitute a novel approach to maintain ACE2 compensatory activity and reduce hypertension. To test this hypothesis, we will use state-of-the-art in vitro and in vivo, molecular, cellular and pharmacological tools combined with unique transgenic and knockout models of hypertension. The results of the present investigation will provide new therapeutic approaches for the treatment of hypertension and a new set of tools for the VA health care system.

在美国，高血压的患病率高于33%，高血压是一个主要的危险因素 心血管疾病(CVD)和全球死亡率，因此仍然是一个日益重要的问题 医疗和公共卫生问题。根据退伍军人事务(VA)研究和办公室 发展，心血管疾病，包括高血压，是美国的头号杀手， 退伍军人医疗保健系统的住院原因和残疾的主要原因。近期 研究已经证明，高血压发生的年龄比过去更年轻，现在影响 处于部署年龄的个人和未来的退伍军人。高血压对退伍军人也很重要 因为它影响了60%的65岁以上的人，而且它与许多疾病有关， 比如糖尿病，以及生活习惯，比如吸烟，这些都有助于糖尿病的发展。美国政府的角色 脑肾素-血管紧张素系统在维持正常血压和高血压中的作用 导致高血压的神经-心血管失调已被牢固地确立。 血管紧张素(Ang)-II通过其1型受体(AT1R)促进交感神经增加 活动，盐和水的重吸收，血管收缩，醛固酮和加压素的释放和 炎症，所有这些都会导致高血压。血管紧张素转换酶2(ACE2)， 这一系统的最新成员之一对激活 RAS。大量研究表明，血管紧张素转换酶2的过度表达阻止了实验性 高血压。然而，我们的实验室报道，Ang-II介导ACE2的内化和 通过AT1R激活的降解，通过亮肽素预处理而防止的效果， 溶酶体抑制剂。ACE2代偿活性丧失的详细机制 还没有被调查。这项提议旨在针对这一负责 ACE2下调，最初由我们的小组描述，以设计创新的战略 高血压的治疗。这些策略的有效性将通过它们的能力来评估 神经源性血管紧张素转换酶抑制血管紧张素转换酶内化和保护血管紧张素转换酶2代偿 高血压。我们的初步数据显示，ACE2 C-末端的泛素化是一个主要的 导致ACE2降解的机制。此外，β-arrestin途径的刺激 AT1R偏向激动剂可增加神经元中ACE2的活性。最后，ACE2内化可能 涉及G蛋白偶联受体家族的其他成员，如缓激肽B1 受体(B1R)与RAS相互作用。因此，本工作的假设是AT1R和B1R 通过影响ACE2表达的多个结合伙伴钝化ACE2的补偿活性 水平、亚细胞定位和酶活性。药物的药理和基因靶向 这些结合伙伴可能构成一种维持ACE2补偿活性的新方法 并降低高血压。为了验证这一假设，我们将使用体外和体内最先进的技术， 分子、细胞和药理工具与独特的转基因和敲除相结合 高血压模型。目前的调查结果将提供新的治疗方法 治疗高血压的方法和退伍军人保健系统的一套新工具。

项目成果

Central administration of TRV027 improves baroreflex sensitivity and vascular reactivity in spontaneously hypertensive rats.

• DOI: 10.1042/cs20180222
• 发表时间: 2018-07-31
• 期刊: Clinical science (London, England : 1979)
• 作者: Carvalho-Galvão A;Ogunlade B;Xu J;Silva-Alves CRA;Mendes-Júnior LG;Guimarães DD;Cruz JC;Queiroz TM;Balarini CM;Braga VA;Filipeanu CM;Lazartigues E;de França-Silva MDS
• 通讯作者: de França-Silva MDS