School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, Georgia, USA.
Department of Epidemiology and Biostatistics, University of Georgia, Athens, Georgia, USA.
Clin Pharmacol Ther. 2021 Apr;109(4):1092-1103. doi: 10.1002/cpt.2177. Epub 2021 Mar 10.
ACE inhibitors (ACEis) and angiotensin receptor blockers (ARBs) are standard-of-care treatments for hypertension and diabetes, common comorbidities among hospitalized patients with coronavirus disease 2019 (COVID-19). Their use in the setting of COVID-19 has been heavily debated due to potential interactions with ACE2, an enzyme that links the pro-inflammatory and anti-inflammatory arms of the renin angiotensin system, but also the entryway by which severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) invades cells. ACE2 expression is altered by age, hypertension, diabetes, and the virus itself. This study integrated available information about the renin angiotensin aldosterone system (RAAS) and effects of SARS-CoV-2 and its comorbidities on ACE2 into a mechanistic mathematical model and aimed to quantitatively predict effects of ACEi/ARBs on the RAAS pro-inflammatory/anti-inflammatory balance. RAAS blockade prior to SARS-CoV-2 infection is predicted to increase the mas-AT1 receptor occupancy ratio up to 20-fold, indicating that in patients already taking an ACEi/ARB before infection, the anti-inflammatory arm is already elevated while the pro-inflammatory arm is suppressed. Predicted pro-inflammatory shifts in the mas-AT1 ratio due to ACE2 downregulation by SARS-CoV-2 were small relative to anti-inflammatory shifts induced by ACEi/ARB. Predicted effects of changes in ACE2 expression with comorbidities of diabetes, hypertension, or aging on mas-AT1 occupancy ratio were also relatively small. Last, predicted changes in the angiotensin (Ang(1-7)) production rate with ACEi/ARB therapy, comorbidities, or infection were all small relative to exogenous Ang(1-7) infusion rates shown experimentally to protect against acute lung injury, suggesting that any changes in the ACE2-Ang(1-7)-mas arm may not be large enough to play a major role in COVID-19 pathophysiology.
血管紧张素转换酶抑制剂（ACEi）和血管紧张素受体阻滞剂（ARB）是治疗高血压和糖尿病的标准治疗方法，这两种疾病是住院 COVID-19 患者的常见合并症。由于它们可能与 ACE2 相互作用，ACE2 是连接肾素血管紧张素系统促炎和抗炎臂的酶，也是严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）入侵细胞的途径，因此它们在 COVID-19 中的使用受到了广泛的争论。ACE2 的表达受年龄、高血压、糖尿病和病毒本身的影响。本研究将肾素血管紧张素醛固酮系统（RAAS）的现有信息以及 SARS-CoV-2 及其合并症对 ACE2 的影响整合到一个机制数学模型中，并旨在定量预测 ACEi/ARB 对 RAAS 促炎/抗炎平衡的影响。在 SARS-CoV-2 感染之前进行 RAAS 阻断预计会使 mas-AT1 受体占有率增加 20 倍，表明在感染前已经服用 ACEi/ARB 的患者中，抗炎臂已经升高，而促炎臂受到抑制。由于 SARS-CoV-2 下调 ACE2，预计 mas-AT1 比值的促炎转移相对较小，而 ACEi/ARB 诱导的抗炎转移较大。由于糖尿病、高血压或衰老等合并症引起的 ACE2 表达变化对 mas-AT1 占有率的预测影响也相对较小。最后，ACEi/ARB 治疗、合并症或感染引起的血管紧张素（Ang（1-7））产生率的预测变化与实验中显示的保护急性肺损伤的外源性 Ang（1-7）输注率相比均较小，表明 ACE2-Ang（1-7）-mas 臂的任何变化都可能不足以在 COVID-19 病理生理学中发挥主要作用。
