Characterizing the RyR2-Mediated Cardiac Pathophysiology of COVID-19 in Rodent Models

Overview

As of 2024, COVID -19 has resulted in over one million deaths in the U.S. and seven million globally. While research has primarily focused on pulmonary manifestations, cardiovascular complications, and their pathogenesis remain a significant yet underexplor ed consequence of SARS-CoV-2 infection. This study characterized the pathogenesis of COVID-19-induced cardiac dysfunction, specifically the role of the ryanodine receptor (RyR2), an intracellular calcium release channel on the sarcoplasmic reticulum in cardiomyocytes. Additionally, this study evaluated s107 as a potential therapeutic agent to reduce SARS -CoV-2-induced cardiac dysfunction. Protein lysates and immunoprecipitates were isolated from the cardiac tissue of control and SARS -CoV- 2-infected mice and Syrian golden hamsters. Quantitative proteomics revealed discernable protein dysregulation in SARS -CoV-2-infected samples, particularly proteins that play a role in RyR2 dysfunction. Western blotting displayed increased markers of post -translational modifications to RyR2, indicative of structural changes to the channel and RyR2 Ca 2+ leak. This Ca2+ leak was then confirmed through a calcium spark analysis. Lastly, increased interstitial fibrosis (1.5-fold in mice and 2 -fold in hamsters) and decreased ejection fraction (.73 -fold) were observed in SARS-CoV-2 infected rodents. Treatment with the RyR2 stabilizer, s107, significantly improved calcium homeostasis by stabilizing RyR2 and improved cardiac function by restoring ejection fraction. These findings confirm the role of RyR2 in cardiac pathophysiology associated with COVID-19 and highlight s107’s therapeutic potential in reducing SARS-CoV-2-induced RyR2 calcium leak and improving cardiac function. This study sets the stage for future in -vitro investigations and clinical trials, employing s107 to reduce COVID-19 morbidity and mortality. North Carolina