COVID19: SARS-CoV-2 and ACE2 interaction in hypertension

COVID19：SARS-CoV-2 和 ACE2 在高血压中的相互作用

• 批准号: 10398819
• 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: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398819
• 关键词: 2019-nCoV; ACE2; Address; Adult; Affect; Age; Aldosterone; American; Angiotensin II Receptor; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Anosmia; Blood Pressure; Brain; Brain hemorrhage; COVID-19; COVID-19 mortality; COVID-19 pandemic; COVID-19 susceptibility; Carboxypeptidase; Cardiovascular system; Cell Culture Techniques; Cell membrane; Cells; Clinical; Clinical Trials; Complex; Coronary heart disease; Coronavirus; Coronavirus Infections; Coronavirus spike protein; Data; Diabetes Mellitus; Down-Regulation; Enzymes; Epithelial Cells; Event; Experimental Models; Exposure to; Family; Human; Human Resources; Hypertension; In Vitro; Incidence; Individual; Infection; Inflammation; Ischemia; Knock-in Mouse; Life Style; Light; Losartan; Lung; Lysosomes; Maintenance; Mediating; Medical; Molecular; Mus; Neurons; Obesity; Patients; Peptides; Peptidyl-Dipeptidase A; Pharmaceutical Preparations; Pharmacology; Population; Predisposition; Prevention; Public Health; Receptor Activation; Receptor, Angiotensin, Type 1; Recording of previous events; Renin-Angiotensin System; Reporting; Resources; Risk Factors; Role; SARS-CoV-2 infection; Sodium Chloride; Symptoms; System; Telemetry; Testing; Therapeutic; Time; Transgenic Mice; Ubiquitination; Up-Regulation; Vasodilator Agents; Vasopressins; Veterans; Viral; Virus; Virus Diseases; Water; active duty; angiotensin I (1-7); base; comorbidity; diabetic patient; high risk; hypertension treatment; hypertensive; improved; in vivo; infection rate; inhibitor; member; mouse model; neurogenic hypertension; novel therapeutic intervention; obese patients; overexpression; patient subsets; preservation; prevent; receptor; therapeutic evaluation; tool; vascular bed; vasoconstriction

The current COVID-19 pandemic is one of the most disruptive events in human history, caused by the SARS- CoV-2 virus, member of the coronavirus family that uses angiotensin converting enzyme 2 (ACE2), a transmembrane carboxypeptidase identified as a member of the renin-angiotensin system (RAS) as an entry point to the cells. Clinical reports suggest that pre-existing conditions such as hypertension, diabetes and obesity predispose to COVID-19 mortality. Considering that these co-morbidities are highly prevalent in Veterans and active duty personnel, these populations are at high risk of infection by SARS-CoV-2. The role of the brain RAS in the maintenance of normal blood pressure (BP) and in the neuro-cardiovascular dysregulation leading to hypertension has been firmly established. In addition, anosmia (loss of smell) is an early symptom of COVID-19 suggesting the brain is a primary target for SARS-CoV-2 infection. For the treatment of hypertension, two of the most popular drug choices are ACE inhibitors (ACEI) and angiotensin-II (Ang-II) type 1 receptor (AT1R) blockers (ARB). None of these classes of drugs have a direct effect on ACE2 activity, but there is evidence indicating that they may alter long-term ACE2 expression levels and subcellular localization, suggesting that patients taking these medications may be subject to more severe infections with SARS-CoV-2. Thus, clear data on the relationship between ACE2 plasma membrane levels, SARS-CoV-2 and co-expression of other RAS members are required to promptly adapt the therapy in this subset of patients. Beyond establishing ACE2 as a critical player in the prevention of neurogenic hypertension, our group was the first to report that Ang-II mediates ACE2 internalization and degradation via AT1R activation. Thus, the hypothesis of this proposal is that ACE2-AT1R complexes enhance SARS-CoV-2 infection in hypertensive Veterans while RAS blockers prevent ACE2 internalization and coronavirus infection. Taking advantage of unique resources, including a humanized transgenic mouse expressing human ACE2 constitutively, we will determine whether AT1R contribute to SARS- CoV-2 infection and whether ACEI and ARB reduce the incidence of COVID-19.

当前的Covid-19大流行是人类历史上最具破坏性的事件之一，由SARS- COV-2病毒，使用血管紧张素转化酶2（ACE2）的冠状病毒家族的成员 跨膜羧肽酶被识别为肾素 - 血管紧张素系统（RAS）的成员 指向细胞。临床报告表明，高血压，糖尿病和肥胖症等先前存在的疾病 倾向于19号死亡率。考虑到这些合并症在退伍军人和 现役人员，这些人群有SARS-COV-2感染的高风险。大脑拉斯的作用 在维持正常血压（BP）和神经性血管血管失调中，导致 高血压已经牢固确立。此外，厌食（气味丧失）是Covid-19的早期症状 表明大脑是SARS-COV-2感染的主要目标。为了治疗高血压，两个 最受欢迎的药物选择是ACE抑制剂（ACEI）和血管紧张素II（ANG-II）1型受体（AT1R）阻滞剂 （ARB）。这些类别的药物都不对ACE2活性有直接影响，但是有证据表明 它们可能会改变长期ACE2表达水平和亚细胞定位，表明患者接受 这些药物可能会受到SARS-COV-2的更严重感染。因此，清除有关 ACE2质膜水平，SARS-COV-2与其他RAS成员共表达之间的关系 需要在这一部分患者中迅速适应疗法。除了将ACE2建立为关键 预防神经源性高血压的玩家，我们的小组是第一个报告ANG-II介导ACE2的人 通过AT1R激活进行内在化和降解。因此，该提议的假设是ACE2-AT1R 复合物增强了高血压退伍军人的SARS-COV-2感染，而RAS阻滞剂则阻止了ACE2 内在化和冠状病毒感染。利用独特的资源，包括人性化的资源 构成性地表达人ACE2的转基因小鼠，我们将确定AT​​1R是否有助于SARS- COV-2感染以及ACEI和ARB是否降低了COVID-19的发生率。