Renin-Angiotensin System Blockade Influences ACE2 in Human Type II Pneumocytes

Abstract

\n Rationale—Angiotensin converting enzyme (ACE) 2 and the transmembrane protease serine 2 (TMPRSS2) are key for cellular entry of the type 2 coronavirus that causes severe acute respiratory syndrome (SARS-CoV2), the etiological agent of coronavirus-19 disease (COVID-19). There has been a growing concern that renin-angiotensin system (RAS) blockade with ACE inhibitors (ACEIs) or type 1 angiotensin (Ang II) receptor blockers (ARBs) increases ACE2 expression and then elevate patient susceptibility to SARS-CoV-2. However, evidence about RAS blockade and ACE2 in human lung are lacking.Objective– To investigate RAS blockade on ACE2 and TMPRSS2 in type II pneumocytes of human lung parenchymal of untreated and ACEI/ARB-treated hypertensive subjects.Methods and Results– ACE2 and TMPRSS2 protein expression were measured by immunohistochemistry. We found that smoking and RAS blockade influence on the percentage of human ACE2-expressing type II pneumocytes (p= 0.026). Smokers subjects under RAS blockade treatment exhibited higher percentage of ACE2-expressing type II pneumocytes than normotensive ones. Within the ACEI/ARB-treated group, the percentage of ACE2-expressing type II pneumocytes was higher in smokers than never smokers. A significant association between ACE2 immunostaining intensity and smoking on subjects over 60 years old was found (p= 0.05): older smokers exhibited higher ACE2 protein levels compared to youngers. The percentage of TMPRSS2-expressing type II pneumocytes was greater in men than women (p= 0.026) and in subjects under 60 years old (p= 0.040) and trend to be higher in ACEI/ARB-treated subjects than normotensives (p= 0.060). A significant association between TMPRSS2 immunostaining intensity with smoking and age or with RAS blockade and age or with RAS blockade and smoking was observed. Older or smokers subjects under ACEI/ARB treatment exhibited higher TMPRSS2 protein levels than youngers or never smokers.Conclusions—ACE2 and TMPRSS2 are influenced by smoking and ACEI/ARB treatment. These findings help explain the increased susceptibility to COVID-19 in subjects with treated cardiovascular-related pathologies.