Abstract 539: Lipogenesis Regulates the Response of Cardiac Muscle to Ischemic Stress Through Sarcoplasmic Reticulum Calcium Atpase

Dysfunctional calcium homeostasis is a hallmark of heart failure, a sequela of myocardial infarction (MI). Previous research has shown that mice deficient in cardiac fatty acid synthase (FAS), the rate-limiting enzyme for de novo lipogenesis, have dysfunctional calcium signaling and a predisposition to heart failure. Yet the mechanisms linking endogenous lipid synthesis, myocardial calcium homeostasis, and cardiac function remain poorly understood. A major step in calcium handling is the transport of cytosolic calcium back into the sarcoplasmic reticulum (SR) by sarcoplasmic reticulum calcium ATPase (SERCA), and recent evidence suggests that SR lipid composition can affect SERCA function. To determine whether FAS plays a role in SERCA activity in the heart, we evaluated FASKard ( FAS K nockout in the Myoc ard ium) mice in the setting of experimental myocardial infarction (MI). Deletion of heart FAS caused a decrease in SERCA activity in younger adult (4 months) and aged (12 months) mice when compared to control (Ctrl) mice of the same age. Lipidomic analysis of the SR showed the reduced SERCA activity in FASKard mice was due to an altered SR phospholipid composition, leading to an imbalance of SR phosphatidylcholine to phosphatidylethanolamine phospholipid ratios. This altered ratio of SR phospholipids was due to a decrease in the abundance of specific phosphatidylethanolamine phospholipid species. MI caused a decrease in SERCA activity in both Ctrl and FASKard mice hearts. FASKard mice after MI had impaired survival with concomitantly decreased SERCA activity compared to Ctrl mice after MI. FASKard MI mice also had a perturbed ratio of SR phosphatidylcholine to phosphatidylethanolamine phospholipids compared to Ctrl MI mice, due to a decrease in certain phosphatidylethanolamine phospholipids. Additionally, MI induced FAS expression in the myocardium. These findings suggest that myocardial de novo lipogenesis is critical to the maintenance of the SR phospholipid composition, SR-mediated calcium homeostasis, and blunting the development of heart failure, particularly ischemic cardiomyopathy. Furthermore, FAS regulation of the SR lipid composition represents a novel therapeutic strategy in the treatment of heart failure.