Brooks Steven D, Smith Rachel L, Moreira Aline S, Ackerman Hans C
Physiology Unit, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, Rockville, MD, United States.
Front Pharmacol. 2022 Mar 10;13:798349. doi: 10.3389/fphar.2022.798349. eCollection 2022.
Angiotensin-converting enzyme 2 (ACE2) is the established cellular receptor for SARS-CoV-2. However, it is unclear whether ACE1 inhibitors (e.g., lisinopril) or angiotensin receptor blockers (e.g., losartan) alter tissue ACE2 expression. This study sought to determine whether lisinopril or losartan, as monotherapies or in combination, changes tissue levels of ACE2 in healthy male and female mice. Mice received lisinopril (10 mg/kg/day), losartan (10 mg/kg/day), or both for 21 days via drinking water. A control group received water without drug. The ACE2 protein index (ACE2 protein/total protein) was determined on the small intestine, lung, kidney, and brain. Oral lisinopril increased the ACE2 protein index across all tissues ( < 0.0001 vs. control). In contrast, the combination of lisinopril plus losartan did not increase ACE2 levels in any tissue ( = 0.89 vs. control) and even decreased tissue expression of the gene ( < 0.001 vs. control). Tissue ACE2 remained elevated in the mice 21 days after cessation of lisinopril ( = 0.02). Plasma ACE2 did not correlate with the ACE2 protein index in any tissue. A sex difference was observed: kidney ACE2 levels were higher in male than in female mice ( < 0.0001). Oral lisinopril increases ACE2, the cellular receptor for SARS-CoV-2, in tissues that are relevant to the transmission and pathogenesis of COVID-19. Remarkably, the addition of losartan prevented lisinopril-induced increases in ACE2 across tissues. These results suggest that ACE inhibitors and angiotensin receptor blockers interact to determine tissue levels of ACE2.
血管紧张素转换酶2（ACE2）是已确定的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的细胞受体。然而，尚不清楚血管紧张素转换酶1（ACE1）抑制剂（如赖诺普利）或血管紧张素受体阻滞剂（如氯沙坦）是否会改变组织中ACE2的表达。本研究旨在确定赖诺普利或氯沙坦单药治疗或联合使用是否会改变健康雄性和雌性小鼠组织中ACE2的水平。小鼠通过饮水接受赖诺普利（10毫克/千克/天）、氯沙坦（10毫克/千克/天）或两者联合治疗21天。对照组接受不含药物的水。测定小肠、肺、肾和脑中的ACE2蛋白指数（ACE2蛋白/总蛋白）。口服赖诺普利可提高所有组织中的ACE2蛋白指数（与对照组相比，<0.0001）。相比之下，赖诺普利加氯沙坦联合使用并未增加任何组织中的ACE2水平（与对照组相比，=0.89），甚至降低了该基因的组织表达（与对照组相比，<0.001）。在停用赖诺普利21天后，小鼠组织中的ACE2仍保持升高（=0.02）。血浆ACE2与任何组织中的ACE2蛋白指数均无相关性。观察到性别差异：雄性小鼠肾中的ACE2水平高于雌性小鼠（<0.0001）。口服赖诺普利可增加与2019冠状病毒病传播和发病机制相关组织中的ACE2（SARS-CoV-2的细胞受体）。值得注意的是，添加氯沙坦可阻止赖诺普利诱导的各组织中ACE2的增加。这些结果表明，ACE抑制剂和血管紧张素受体阻滞剂相互作用以决定组织中ACE2的水平。
