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: 10152313
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152313
• 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; Cleaved cell; 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; improved; in vivo; infection rate; inhibitor/antagonist; 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引起- CoV-2病毒是冠状病毒家族的成员，使用血管紧张素转换酶2（ACE 2）， 跨膜羧肽酶被鉴定为肾素-血管紧张素系统（RAS）的成员， 指向细胞。临床报告表明，预先存在的疾病，如高血压，糖尿病和肥胖症， 容易导致COVID-19死亡。考虑到这些合并症在退伍军人中非常普遍， 现役人员，这些人群感染SARS-CoV-2的风险很高。大脑RAS的作用 在维持正常血压（BP）和神经-心血管失调中， 高血压已经被确定。此外，嗅觉丧失（嗅觉丧失）是COVID-19的早期症状 这表明大脑是SARS-CoV-2感染的主要靶点。对于高血压的治疗， 最流行的药物选择是ACE抑制剂（ACEI）和血管紧张素II（Ang-II）1型受体（AT 1 R）阻断剂 （ARB）。这些类别的药物对ACE 2活性都没有直接影响，但有证据表明， 它们可能会改变长期ACE 2表达水平和亚细胞定位，这表明服用ACE 2的患者 这些药物可能会导致更严重的SARS-CoV-2感染。因此，关于 ACE 2质膜水平、SARS-CoV-2和其他RAS成员共表达之间的关系 需要迅速调整该患者亚组的治疗。除了将ACE 2确立为关键的 作为预防神经源性高血压的重要分子，我们的研究小组首次报道了Ang-II介导ACE 2 通过AT 1 R活化的内化和降解。因此，该提议的假设是ACE 2-AT 1 R 复合物增强高血压退伍军人的SARS-CoV-2感染，而RAS阻断剂预防ACE 2 内化和冠状病毒感染。利用独特的资源，包括人性化的 在组成型表达人ACE 2的转基因小鼠中，我们将确定AT 1 R是否有助于SARS- CoV-2感染以及ACEI和ARB是否能降低COVID-19的发病率。