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

当前的新冠肺炎疫情是人类历史上最具破坏性的事件之一，由非典引发-- 冠状病毒2型，冠状病毒家族的成员，使用血管紧张素转换酶2(ACE2)，a 跨膜羧肽酶被确认为肾素-血管紧张素系统(RAS)的一员 指向单元格。临床报告表明，高血压、糖尿病和肥胖等先前存在的疾病 易患新冠肺炎死亡率。考虑到这些并存疾病在退伍军人和 这些人是现役人员，感染SARS-CoV-2的风险很高。脑RAS的作用 在维持正常血压(BP)和神经-心血管失调导致 高血压已经站稳了脚跟。此外，嗅觉障碍(嗅觉丧失)是新冠肺炎的早期症状 这表明大脑是SARS-CoV-2感染的主要目标。对于高血压的治疗，有两种 最受欢迎的药物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)。这些类别的药物都不会直接影响血管紧张素转换酶2的活性，但有证据表明 它们可能会改变ACE2的长期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，就可以清除 血管紧张素转换酶2质膜水平与SARS-CoV-2及其他RAS成员共表达的关系 被要求迅速适应这一亚群患者的治疗。除了将ACE2确立为关键 在神经源性高血压的预防中发挥作用，我们小组首次报道了Ang-II介导血管紧张素转换酶2 通过AT1R激活内化和降解。因此，这一提议的假设是ACE2-AT1R 复合体增强高血压退伍军人SARS-CoV-2感染而RAS阻滞剂预防ACE2 内化与冠状病毒感染。利用独特的资源，包括人性化的 我们将确定AT1R是否在SARS中起作用。 冠状病毒2型感染以及血管紧张素转换酶I和ARB是否降低新冠肺炎的发生率。

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.