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%，是导致高血压的主要危险因素。 心血管疾病（CVD）和全球死亡率，因此仍然是一个越来越重要的 医疗和公共卫生问题。根据退伍军人事务部（VA）研究和 发展，心血管疾病，包括高血压，是美国的头号杀手， 在VA医疗保健系统住院的原因和残疾的主要原因。最近 研究表明，高血压发生在比过去更年轻的年龄，现在影响到 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，并且与许多疾病有关， 比如糖尿病，还有生活习惯，比如吸烟，这些都是导致糖尿病的原因。的作用 脑肾素-血管紧张素系统（RAS）在维持正常血压（BP）和 导致高血压的神经-心血管失调已经被牢固地确立。 血管紧张素（Ang）-II，通过其1型受体（AT 1 R），促进交感神经的增加， 活性、盐和水重吸收、血管收缩、醛固酮和加压素释放， 炎症，所有这些都会导致高血压。血管紧张素转换酶2（ACE 2）， 该系统最新确定的成员之一对激活起着补偿作用， RAS。大量研究表明，ACE 2过表达阻止了实验性的 高血压然而，我们的实验室报道Ang-II介导ACE 2内化， 通过AT 1 R活化的降解，通过亮抑酶肽预处理防止的作用， 溶酶体抑制剂导致ACE 2代偿活性丧失的详细机制 尚未被调查。这项建议旨在针对这一新机制， ACE 2下调，最初由我们的小组描述，以设计创新的策略， 治疗高血压。这些战略的有效性将通过其以下能力来评估： 防止ACE 2内化并在神经源性损伤的背景下保持ACE 2代偿性 高血压我们的初步数据表明，ACE 2的C-末端的泛素化是一个主要的 导致ACE 2降解的机制。此外，用β-arrestin刺激β-arrestin通路， AT 1 R偏向激动剂增加神经元中ACE 2活性。最后，ACE 2内化可能 涉及G蛋白偶联受体家族（GPCR）的其他成员，如缓激肽B1 受体（B1 R）与RAS相互作用。因此，这项工作的假设是，AT 1 R和B1 R 通过影响ACE 2表达的多个结合伴侣减弱ACE 2的代偿活性 水平、亚细胞定位和酶活性。药理学和遗传靶向 这些结合伴侣可能构成维持ACE 2代偿活性的新途径 降低高血压。为了验证这一假设，我们将使用最先进的体外和体内， 分子、细胞和药理学工具结合独特的转基因和敲除 高血压模型。本研究的结果将提供新的治疗方法 治疗高血压的方法和VA医疗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