Oral Lisinopril Raises Tissue Levels of ACE2, the SARS-CoV-2 Receptor, in Healthy Male and Female Mice.

Steven D Brooks,Hans C Ackerman,Rachel L Smith,Aline S Moreira

doi:10.3389/fphar.2022.798349

Abstract

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 (p < 0.0001 vs. control). In contrast, the combination of lisinopril plus losartan did not increase ACE2 levels in any tissue (p = 0.89 vs. control) and even decreased tissue expression of the Ace2 gene (p < 0.001 vs. control). Tissue ACE2 remained elevated in the mice 21 days after cessation of lisinopril (p = 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 (p < 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.

Highlights

Angiotensin-converting enzyme 2 (ACE2) is an established receptor and entry point for both SARSCoV-1 and the novel SARS-CoV-2 coronavirus (Li et al, 2003; Kuba et al, 2005; Hoffmann et al, 2020)
The primary goal of this study was to determine whether lisinopril, an oral ACE inhibitor, or losartan, an oral angiotensin receptor blockers (ARBs), changes the tissue abundance of ACE2, and whether these changes resolve after cessation of the drug
These results provide controlled experimental data demonstrating the impact of ACE inhibition and angiotensin receptor blockade on tissue ACE2 expression in mice and highlight a potential benefit of ACE inhibitor/ARB combination therapy in the setting of a SARS-CoV-2 pandemic

Summary

Introduction

Angiotensin-converting enzyme 2 (ACE2) is an established receptor and entry point for both SARSCoV-1 and the novel SARS-CoV-2 coronavirus (Li et al, 2003; Kuba et al, 2005; Hoffmann et al, 2020). The spike proteins on the viral envelope bind the ACE2 receptor, and the virus replicates efficiently in cells expressing ACE2 (Li et al, 2003). Human tissue histological profiling reveals ACE2 to be highly expressed on lung alveolar epithelial cells and on enterocytes of the small intestine, as well as on arterial and venous endothelium (Hamming et al, 2004). SARS-CoV-2 can enter vascular endothelium in engineered human blood vessel organoids and human kidney organoids via ACE2 (Monteil et al, 2020). SARS-CoV-2 is associated with endothelial inflammation (Cao and Li, 2020; Varga et al, 2020), which may give rise to the clinical findings of thromboembolism (Oudkerk et al, 2020) and disseminated intravascular coagulation (Tang et al, 2020)

Objectives

Methods

Results

Conclusion