As illustrated in Graphical Abstract, SARS-CoV-2 initiates cell entry by binding of its spike (S) protein to the ACE2 receptor on the host cell membrane. ACE2 is expressed in a variety of tissues, including the respiratory tract, cardiac fibroblasts, cardiomyocytes, vascular smooth muscle cells, kidneys, intestines, and central nervous system [2]. Following the binding of the S protein to ACE2, SARS-CoV-2 is internalized by the host cell, which leads to the downregulation of ACE2 expression on the cell surface. SARS-CoV-2 entry into cells and the subsequent downregulation of ACE2 can trigger localized tissue inflammation. A study using cardiac magnetic resonance imaging reported that myocardial injury occurs with high frequency [3].

ACE2 is a critical regulator of the renin-angiotensin-aldosterone system (RAAS), and its downregulation due to SARS-CoV-2 infection disrupts RAAS balance, exacerbating inflammation [4]. This dysregulation has been identified as a key factor contributing to severe coronavirus disease 2019 (COVID-19) outcomes. Thus, RAAS inhibitors, such as ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), have been investigated as potential therapeutic agents for COVID-19. However, concerns have been raised that ACEIs and ARBs may upregulate ACE2 expression on the cell membrane, potentially increasing susceptibility to SARS-CoV-2 infection [5]. These concerns have been amplified with the emergence of the Omicron variant, which exhibits higher affinity for ACE2 [1], and thus, warrants further evaluation of the safety of these medications.