Host: The Japanese Society of Toxicology
Name : The 49th Annual Meeting of the Japanese Society of Toxicology
Date : June 30, 2022 - July 02, 2022
Heart disease is a major aggravating symptom of the new coronavirus infection (COVID-19) and a major risk factor for COVID-19 aggravation. We previously reported that the membrane protein-protein interaction between transient receptor potential canonical (TRPC) 3 channel and NADPH oxidase 2 (Nox2) mediates the progression of heart failure with cardiac remodeling. Here, we found that the exposure of rodent cardiomyocytes to various COVID-19 aggravation risk factors, such as hyperglycemia, smoking, and anticancer agents, increased expression level of angiotensin converting enzyme (ACE) 2, by forming TRPC3-Nox2 protein complex. Pharmacological intervention of TRPC3-Nox2 complex formation suppressed not only cardiomyocyte atrophy but also increased ACE2 mRNA expression due to anticancer drug treatment. Therefore, we screened the top 13 approved drugs that can suppress TRPC3-Nox2 complex formation to identify a drug that can additionally suppress SARS-CoV-2-derived spike protein-induced ACE2 internalization. We found that the tricyclic antidepressant, clomipramine, potently suppressed SARS-CoV-2 infection of human iPS cell-derived cardiomyocytes, as well as cardiac contractile dysfunction and metabolic dysfunction. These results strongly suggest that risk factors for COVID-19 aggravation cause cardiac disorder through increased expression of ACE2, and that approved drugs that block this pathway can be indicated for the prevention and treatment of COVID-19 cardiac severity.
