Abstract 16026: Cardiomyocyte-Specific Adipose Triglyceride Lipase Over-Expression Impairs Functional Recovery of the Reperfused Myocardium Following Ischemia
The influence of cardiac triacylglycerol (TAG) catabolism on myocardial function during reperfusion following ischemia is relatively understudied. To address this, levels of adipose triglyceride lipase (ATGL), the rate-limiting enzyme for TAG hydrolysis, were assessed in hearts from C57BL6 mice perfused ex vivo in the working mode aerobically for 30 min, followed by 18 minutes of ischemia and 40 minutes of reperfusion with a buffer containing 5 mM glucose, 1.2 mM palmitate and 50 microunits/ml insulin. ATGL protein expression and cardiac TAG content were increased following ischemia-reperfusion (I-R) (aerobic vs. I-R; 0.766±0.06 vs. 1.221±0.08 nmol TAG per mg heart weight, mean±SEM, n=4-5, p<0.01), suggesting augmented lipid turnover. To determine whether increased ATGL-mediated TAG lipolysis is beneficial or detrimental for the functional recovery of the reperfused myocardium, WT and cardiac-specific ATGL over-expressing (MHC-ATGL) mouse hearts were subjected to an identical ex vivo I-R protocol. During the pre-ischemic period, MHC-ATGL hearts exhibited a 70% reduced myocardial TAG content (n=6, p<0.0001), a 2.7-fold increase in glycolysis (n=4-5, p<0.01), a 1.5-fold increase in glucose oxidation (n=4-5, p<0.01), and a significant decrease in palmitate oxidation (WT vs. MHC-ATGL; 1010±146 vs. 712±107 nmol per gram dry weight per min, mean±SEM, n=4-5, p<0.01) without alterations in cardiac function. However, following I-R, MHC-ATGL but not WT hearts exhibited a significant decrease in palmitate oxidation but not glycolysis and glucose oxidation. Indices of cardiac function following I-R were significantly reduced in MHC-ATGL hearts (LV minute work; WT vs. MHC-ATGL; 6.7±1.3 vs. 0.19±0.05 Joules per g dry weight, mean±SEM, n=5-6, p<0.05), which was accompanied by decreased ATP-AMP and PCr-Cr ratios, demonstrating impaired functional recovery. Ex vivo changes were also recapitulated in an in vivo model of I-R (coronary artery ligation) wherein significantly enhanced necrosis was observed in MHC-ATGL compared to WT hearts, suggesting that enhanced ATGL-mediated TAG hydrolysis and/or reduction in myocardial TAG content is detrimental to contractile recovery following myocardial I-R.
- © 2011 by American Heart Association, Inc.