Testing the Ability of the Drug-Like Compound S1QEL1.719 to Reduce Cardiac Superoxide Damage in Mice
Graduation Year
2026
Document Type
Master's Thesis
Degree
Master of Science
Program
Biological Science
Partner Organization
Buck Institute for Research on Aging
Program Director
Patti Culross, MD, MPH
First Reader
Simon Melov, PhD
Second Reader
Nicolas Martin
Abstract
Cardiovascular disease (CVD) is the number one cause of death worldwide, accounting for 32% of worldwide deaths annually. The prevalence of CVD, such as atrial fibrillation and heart failure, increases with age as cardiac function declines. Oxidative stress due to mitochondrial superoxide production has long been implicated as a primary cause of CVD. The activity of superoxide dismutase (Sod2), the mitochondrial enzyme responsible for preventing superoxide damage via catalyzing its conversion to hydrogen peroxide declines in efficiency with age. To counteract this, drug-like compounds called S1QEL molecules have been designed to prevent the production of superoxide from site Iq within complex I the electron transport chain in mitochondria. In this study, we set out to test the efficacy of the drug-like molecule S1QEL1.719 to ameliorate oxidative stress damage in mouse cardiac tissue. To this end, we used the Myh6-Cre:Sod2tm1smel transgenic mouse strain that could be induced to knockout Sod2 expression to increase mitochondrial oxidative stress within cardiac tissue. S1QEL1.719 was administered to these Sod2 null mice over a period of 12 weeks, and their cardiac physiology was tracked via echocardiography and pulse wave velocity (PWV) doppler imaging to determine if S1QEL1.719 is able to attenuate mitochondrial oxidative stress within cardiac tissue. We found that within the cardiac Sod2 knockout mice, S1QEL1.719 treatment protected against multiple predictors of CVD compared to the non-treated group, including the development of cardiac fibrosis and decline in left ventricle physiological health metrics.