RAAS Blockade and COVID‐19: Mechanistic Modeling of Mas and AT1 Receptor Occupancy as Indicators of Pro‐Inflammatory and Anti‐Inflammatory Balance
RAAS Blockade and COVID‐19: Mechanistic Modeling of Mas and AT1 Receptor Occupancy as Indicators of Pro‐Inflammatory and Anti‐Inflammatory Balance
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RAAS 封锁和 COVID-19：Mas 和 AT1 受体占用的机制建模作为促炎和抗炎平衡的指标
DOI：
10.1002/cpt.2177
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发表时间：
2021
影响因子：
6.7
通讯作者：
Ishaan Dave
中科院分区：
文献类型：
--
作者：
Karen Melissa Hallow;Ishaan Dave
ACE抑制剂（ACEis）和血管紧张素受体阻滞剂（ARB）是高血压和糖尿病的标准治疗药物，这是2019冠状病毒病（COVID-19）住院患者的常见合并症。由于与ACE 2的潜在相互作用，它们在COVID-19背景下的使用一直存在很大争议，ACE 2是一种连接肾素血管紧张素系统的促炎和抗炎臂的酶，也是严重急性呼吸综合征冠状病毒2（SARS-CoV-2）侵入细胞的入口。ACE 2的表达会因年龄、高血压、糖尿病和病毒本身而改变。本研究将有关肾素血管紧张素醛固酮系统（RAAS）和SARS-CoV-2及其合并症对ACE 2影响的现有信息整合到一个机制数学模型中，旨在定量预测ACEi/ARB对RAAS促炎/抗炎平衡的影响。预计SARS-CoV-2感染前RAAS阻断可使mas-AT 1受体占有率增加20倍，表明在感染前已服用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ACE 2导致的mas-AT 1比值的预测促炎性变化相对于ACEi/ARB诱导的抗炎性变化较小。ACE 2表达的变化与糖尿病、高血压或衰老的共病对mas‐ AT 1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））生成率的预测变化均小于实验显示的防止急性肺损伤的外源性Ang（1 - 7）输注速率，表明ACE 2-Ang（1 - 7）-mas组的任何变化可能不足以在COVID-19病理生理学中发挥主要作用。
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.
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影响因子：
8.8
作者：
Klein, Nadine;Gembardt, Florian;Kuebler, Wolfgang M.
通讯作者：
Kuebler, Wolfgang M.
大鼠 1 型血管紧张素 II 受体 mRNA 水平的组织特异性调节。
DOI：
10.1161/01.hyp.28.3.403
发表时间：
1996
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Sechi,LA;Griffin,CA;Giacchetti,G;Valentin,JP;Llorens-Cortes,C;Corvol,P;Schambelan,M
通讯作者：
Schambelan,M
影响因子：
7.3
作者：
Supe, Stefanie;Kohse, Franziska;Walther, Thomas
通讯作者：
Walther, Thomas
DOI：
10.1152/ajprenal.00656.2011
发表时间：
2012-06-01
影响因子：
4.2
作者：
Yamaleyeva, Liliya M.;Gilliam-Davis, Shea;Chappell, Mark C.
通讯作者：
Chappell, Mark C.