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，高血压患病率超过 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，因此仍然是一个日益重要的 医疗和公共卫生问题。根据退伍军人事务部 (VA) 研究与办公室的说法 发展、CVD，包括高血压，是美国的头号杀手， 退伍军人管理局医疗保健系统住院的原因和残疾的主要原因。最近的 研究表明，高血压的发病年龄比以前更年轻，现在影响 达到服役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 60% 的 65 岁以上人群，并且与多种疾病有关， 例如糖尿病，以及有助于其发展的生活习惯，例如吸烟。的作用 脑肾素-血管紧张素系统（RAS）在维持正常血压（BP）和 神经心血管失调导致高血压已被证实。 血管紧张素 (Ang)-II 通过其 1 型受体 (AT1R) 促进交感神经的增强 活性、盐和水重吸收、血管收缩、醛固酮和加压素释放以及 炎症，都会导致高血压。 2 型血管紧张素转换酶 (ACE2)、 该系统最新确定的成员之一对激活 RAS。大量研究表明 ACE2 过度表达会阻碍实验 高血压。然而，我们的实验室报告说，Ang-II 介导 ACE2 内化和 通过 AT1R 激活降解，用亮肽素预处理可以防止这种影响， 溶酶体抑制剂。导致ACE2代偿活性丧失的详细机制 尚未被调查。该提案旨在针对这一新机制负责 ACE2 下调，最初由我们小组描述，旨在设计创新策略 治疗高血压。这些策略的有效性将通过它们的能力来评估 防止 ACE2 内化并在神经源性背景下保留 ACE2 代偿性 高血压。我们的初步数据表明，ACE2 C 末端的泛素化是一个主要的 导致 ACE2 降解的机制。此外，刺激 β-arrestin 通路 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 (GPCR) 的其他成员，例如缓激肽 B1 受体 (B1R) 与 RAS 相互作用。因此，这项工作的假设是 AT1R 和 B1R 通过影响其表达的多个结合伙伴来削弱 ACE2 的补偿活性 水平、亚细胞定位和酶活性。药理学和基因靶向 这些结合伙伴可能构成维持 ACE2 补偿活性的新方法 并降低高血压。为了检验这个假设，我们将使用最先进的体外和体内技术， 分子、细胞和药理学工具与独特的转基因和基因敲除相结合 高血压模型。目前的研究结果将提供新的治疗方法 治疗高血压的方法以及退伍军人管理局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