Presentation description

Cardiovascular disease and resultant heart failure (HF) is the leading cause of mortality in the US, and despite the incidence of HF increasing at greater rates in women, they are less likely to receive evidence-based HF therapies as compared to men, and preclinical HF research studies utilizing female subjects are noticeably underrepresented. Mechanistically, maintaining cardiac myocyte (CM) protein homeostasis (proteostasis) is essential for heart function, and autophagy is critical in the degradation process responsible for CM proteostasis. Previous work from our lab has identified a key regulatory function for the SNARE protein, SNAP23, in CM autophagy, and cardiac-specific deletion of SNAP23 in male mice resulted in acute HF. The purpose of this study is to investigate whether SNAP23 is equally important in female cardiovascular biology or whether it exerts sex-specific actions. Our hypothesis is that the loss of SNAP23 impairs CM autophagy and promotes HF in female mice. Our methods involving in vivo assessments of SNAP23 function in adult female mouse hearts were achieved by using SNAP23fl/fl/fl mice injected with AAV9-cTnT-Cre for CM-specific SNAP23 knockout (SNAP23cKO). Echocardiography was performed to assess cardiac structure and function. Following sacrifice, RNA was extracted from the mouse left ventricular extracts and subjected to qRT-PCR for cardiac pathology and autophagy-related gene expression analysis. Our results demonstrate that four weeks after AAV9 administration, female SNAP23cKO mice had significantly impaired cardiac function and left ventricular dilatation characteristic of HF as compared to control mice. At the molecular level, markers of cardiac pathology were dramatically increased while genes associated with autophagy were decreased. Our conclusion is that SNAP23 is essential for maintaining CM autophagy, and conditional SNAP23 deletion in adult female mice results in heart failure. Thus, SNAP23 represents a potential therapeutic target for protecting against heart failure pathogenesis in both men and women.