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 (ACE2)，是一种 跨膜羧肽酶被鉴定为肾素-血管紧张素系统（RAS）的成员作为条目 指向细胞。临床报告表明，高血压、糖尿病和肥胖等原有疾病 容易导致 COVID-19 死亡。考虑到这些合并症在退伍军人和 现役人员，这些人群感染 SARS-CoV-2 的风险很高。大脑 RAS 的作用 维持正常血压（BP）和神经心血管失调导致 高血压已经根深蒂固。此外，嗅觉丧失（嗅觉丧失）是 COVID-19 的早期症状 表明大脑是 SARS-CoV-2 感染的主要目标。对于高血压的治疗，有两种 最流行的药物选择是血管紧张素转换酶抑制剂 (ACEI) 和血管紧张素 II (Ang-II) 1 型受体 (AT1R) 阻滞剂 （ARB）。这些类别的药物均不会直接影响 ACE2 活性，但有证据表明 它们可能会改变长期 ACE2 表达水平和亚细胞定位，这表明服用 这些药物可能会受到更严重的 SARS-CoV-2 感染。这样一来，清晰的数据 ACE2质膜水平、SARS-CoV-2和其他RAS成员共表达之间的关系 需要立即调整这部分患者的治疗方法。除了将 ACE2 确立为关键 作为预防神经源性高血压的重要参与者，我们课题组率先报道了Ang-II介导ACE2 通过 AT1R 激活进行内化和降解。因此，该提案的假设是 ACE2-AT1R 复合物增强高血压退伍军人的 SARS-CoV-2 感染，而 RAS 阻滞剂可预防 ACE2 内化和冠状病毒感染。利用独特的资源，包括人性化的 组成型表达人 ACE2 的转基因小鼠，我们将确定 AT1R 是否有助于 SARS- CoV-2 感染以及 ACEI 和 ARB 是否会降低 COVID-19 的发病率。