da Silva-Santos Yasmin, Pagni Roberta Liberato, Gamon Thais Helena Martins, de Azevedo Marcela Santiago Pacheco, Darido Maria Laura Goussain, de Oliveira Danielle Bruna Leal, Durigon Edson Luiz, Luvizotto Maria Cecília Rui, Ackerman Hans Christian, Marinho Claudio Romero Farias, Carvalho Leonardo José de Moura, Epiphanio Sabrina
Laboratory of Cellular and Molecular Immunopathology of Malaria, Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-000, Brazil.
Laboratory of Malaria Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, Brazil.
Int J Mol Sci. 2025 Aug 8;26(16):7663. doi: 10.3390/ijms26167663.
The regulation of angiotensin-converting enzyme 2 (ACE2) expression by medications such as ACE inhibitors (ACEis) and angiotensin receptor blockers (ARBs) has raised critical questions regarding their potential benefits and risks during COVID-19. ACE2, a regulator of blood pressure through the renin-angiotensin system (RAS), is the primary receptor for SARS-CoV-2. ACEis and ARBs can modulate ACE2 expression, potentially exacerbating viral load. However, the risks of higher viral load could be mitigated by favorable anti-inflammatory responses associated with ACEi and ARB use, highlighting the complexity of their impact on viral replication and disease outcomes. This study investigates the effects of sustained Losartan monotherapy (ARB) and combination Losartan + Lisinopril (ARB + ACEi) on viral replication, inflammation, lung function, and clinical measures of disease severity in a murine model of severe COVID-19 involving humanized ACE2 transgenic mice infected with SARS-CoV-2 Wuhan strain. Both ARB and ARB + ACEi treatments led to increased ACE2 expression in the lungs and higher viral load post-infection. Despite this, the ARB + ACEi combination improved clinical scores, reduced weight loss and inflammatory cytokine levels, and preserved lung function, though it did not improve survival. Overall, the results of these controlled experiments provide insight into the complex dynamics of ACEi and ARB use in COVID-19; while these drugs induce expression of the ACE2 receptor and increase viral load, they provide compensatory modulation of the inflammatory response that appears to diminish severity of the infection.
血管紧张素转换酶2（ACE2）的表达受血管紧张素转换酶抑制剂（ACEi）和血管紧张素受体阻滞剂（ARB）等药物的调节，这引发了关于它们在2019年冠状病毒病（COVID-19）期间潜在益处和风险的关键问题。ACE2是肾素-血管紧张素系统（RAS）中血压的调节因子，也是严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的主要受体。ACEi和ARB可以调节ACE2的表达，可能会加剧病毒载量。然而，与使用ACEi和ARB相关的有利抗炎反应可能会减轻病毒载量升高的风险，这凸显了它们对病毒复制和疾病结局影响的复杂性。本研究调查了在涉及感染SARS-CoV-2武汉株的人源化ACE2转基因小鼠的重症COVID-19小鼠模型中，持续使用氯沙坦单药治疗（ARB）以及氯沙坦+赖诺普利联合治疗（ARB+ACEi）对病毒复制、炎症、肺功能和疾病严重程度临床指标的影响。ARB和ARB+ACEi治疗均导致肺部ACE2表达增加以及感染后病毒载量升高。尽管如此，ARB+ACEi联合治疗改善了临床评分，减少了体重减轻和炎症细胞因子水平，并保留了肺功能，尽管它没有提高生存率。总体而言，这些对照实验的结果为COVID-19中使用ACEi和ARB的复杂动态提供了见解；虽然这些药物诱导ACE2受体表达并增加病毒载量，但它们对炎症反应提供了代偿性调节，这似乎减轻了感染的严重程度。
