Abstract 19807: Increased Triacylglycerol Synthesis in the Heart Improves Functional Recovery After Ischemia

Abstract

Accumulation of cardiac lipids has been associated with cardiac dysfunction in diabetes and obesity while increased muscle lipid storage in athletes is associated with improved function. We have previously shown that cardiac specific overexpression of diacylglycerol acyltransferase 1 (MHC-DGAT1), the rate limiting enzyme for triacylglycerol (TAG) synthesis, enhances TAG synthesis, reduces ceramide formation, and rescues lipotoxic cardiomyopathy. Using MHC-DGAT1 mice, we tested whether increased TAG synthesis and storage affected cardiac responses to ischemia-reperfusion. A doubling of cardiac TAG content in MHC-DGAT1 (P<0.05; n=4) was not associated with in-vivo cardiac dysfunction or heart size. With dynamic 13C NMR spectroscopy we found a 70% increase of incorporation of 13C labeled fatty acids (FA) into the cardiac TAG pool in MHC-DGAT1 hearts. In isolated Langendorff perfused hearts, rate pressure product (RPP), was similar in MHC-DGAT1 and control (CON) hearts at baseline (BL). When subjected to 25min of no-flow ischemia (ISC), end diastolic pressure rose equivalently in both groups. However, recovery of RPP during reperfusion (REP) was significantly improved in MHC-DGAT1 compared to CON (51±6% vs 28±6%; n=5-6). At the end of REP, 13C NMR spectroscopy of heart extracts suggested decreased exogenous FA oxidation with no change in glucose oxidation in MHC-DGAT1 hearts. Cardiac TAGs, measured in freeze-clamped hearts, remained unchanged in CON during BL, at end ISC, and at end REP (n=3 per time point). Interestingly, despite ~2-fold increase in TAG in MHC-DGAT1 at BL, TAG content depleted to levels similar to CON at end ISC and REP, inferring accelerated TAG lipolysis in MHC-DGAT1 during the ischemic period. Non-esterified fatty acid (NEFA) concentration was not different between the groups at any time point. In conclusion, these results suggest that ischemia-induced activation of lipolysis in MHC-DGAT1 hearts improves functional recovery, in part, by increasing the oxidation of endogenous lipids during reperfusion. These data also suggest a potential secondary role of endogenous lipids to act as signaling molecules to modulate cardiac function.