Abstract 10237: Targeting on Nrf2/Sesn2 Signaling to Rescue Cardiac Dysfunction During High Fat Diet-Induced Obesity

Abstract

Introduction: Obesity increases the chances of developing cardiovascular disease and strokes. The overabundance of adipose tissue that occurs in obese individuals increases oxidative stress, which trigger upregulation of antioxidant proteins, Sesn2 and Nrf2. Hypothesis: Obesity-related oxidative stress triggers cardiac Sesn2 and Nrf2 to function in cardioprotective properties. Methods: Cardiomyocyte specific Sesn2 knock out (cSesn2 -/- ) and overexpression (tTa-tet-Sesn2) C57BL/6J mice, and their wildtype littermates (Sesn2 f/f and tet-Sesn2) were subjected to either a high fat diet (HFD) or chow diet. Seahorse XF Analyzer for mitochondrial function and IonOptix Calcium and Contractility System for cardiomyocytes contractile functions. Results: The inducible cardiomyocyte overexpression of Sesn2 (tTa-tet-Sesn2) versus tet-Sesn2 mice gained less weight with HFD. Echocardiography data showed no significant differences in systolic function between tet-Sesn2 and tTa-tet-Sesn2 with HFD or chow diet. However, HFD induced diastolic dysfunction of tet-Sesn2 but not tTa-tet-Sesn2 hearts. Intriguingly, cardiac Nrf2 levels were upregulated in tTa-tet-Sesn2 but not tet-Sesn2 hearts with HFD. Conversely, cSesn2 -/- versus Sesn2 f/f showed lower Nrf2 levels and greater cardiac dysfunction with HFD. MitoSOX staining demonstrated that tTa-tet-Sesn2 versus tet-Sesn2 maintain redox homeostasis in the heart with HFD, while cSesn2 -/- versus Sesn2 f/f showed more reactive oxygen species (ROS) in the heart with HFD. Mitochondrial respiration was impaired in obese cSesn2 -/- versus Sesn2 f/f cardiomyocytes. Moreover, the contractility and transient calcium flux signaling was impaired in obese cSesn2 -/- versus Sesn2 f/f cardiomyocytes. tTa-tet-Sesn2 versus tet-Sesn2 cardiomyocytes demonstrated resistance to HFD-induced contractile dysfunctions, impaired calcium homeostasis and activation of the inflammation-related signaling NF-κB. Conclusions: Sesn2 and Nrf2 modulate redox homeostasis and inflammatory response during obesity pathogenesis. There is a feedforward loop relationship between Sesn2 and Nrf2 in the heart with HFD-induced obesity. Cardiac Sesn2/Nrf2 signaling ameliorates cardiac dysfunction caused by obesity.