Modulation of ACE2 in experimental hypertension and in response to treatment with ACE inhibitors and ARBs: potential implications for COVID-19 severity and therapeutic targets

• Grant number: 20/07371-8
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: July 01, 2020
• End date: June 30, 2021
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Adriana Castello Costa Girardi
• Grantee: Thiago Matheus Santos Rios
• Host Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated research grant: 16/22140-7 - Molecular bases of renal tubular function and dysfunction, AP.TEM

Abstract

Clinical evidence indicates that hypertensive patients are highly susceptible to infection and the severity of COVID-19, a disease caused by the new SARS coronavirus SARS-Cov-2. The SARS-CoV-2 requires the host protein angiotensin-converting enzyme-2 (ACE2), as a receptor, and the serine protease TMPRSS2, for S protein priming, to gain intracellular entry in the lungs, among other organs in which ACE2 is expressed including heart, kidney, and gut. ACE2, however, is a crucial enzymatic component of the renin-angiotensin system (RAS). ACE2 degrades angiotensin II (Ang II), a peptide with multiple actions that contribute to hypertension development, and generates Ang-(1-7), which antagonizes the effects of Ang II. Moreover, experimental and clinical evidence suggests that RAS blockade by ACE inhibitors (ACEi) and AT1 receptor antagonists (ARBs) may enhance ACE2. In lieu of the fact that many patients with hypertension or other cardiovascular diseases are routinely treated with RAS blockers, new clinical concerns have developed regarding whether these patients are at higher risk for SARS-CoV-2 infection. Notably, there are no studies in animals or humans that have examined the effects of ACEi or BRA on pulmonary ACE2. Considering this scenario, the current study was designed to provide scientific evidence on how tissue and circulating ACE2 is regulated in hypertension and in response to ACEi and ARBs, as well as examine whether gender differences may be involved. (AU)