Abstract 14344: Myocardial Adipose Triglyceride Lipase Over-Expression Improves Systolic Function and Protects Against Pressure Overload-Induced Cardiac Dysfunction
Impaired triacylglycerol (TG) turnover and excess accumulation of intramyocardial TG are associated with poor left ventricular function, suggesting that adequate TG hydrolysis may be essential to maintain proper contractile function. To address the importance of TG catabolism in the regulation of myocardial fatty acid metabolism and function, we generated mice with cardiomyocyte-specific over-expression of adipose triglyceride lipase (MHC-ATGL), an enzyme that is rate-limiting for myocardial TG hydrolysis. Biochemical examination of MHC-ATGL hearts revealed chronically reduced myocardial TG content (WT fed: 23.7±1.2, MHC-ATGL fed: 8.6±1.6 nmol/mg protein, mean±SEM, n=7-8, p<1x10-5) but unchanged levels of long chain acyl-CoAs, ceramides, and diacylglycerols. Oleate oxidation rates were unexpectedly decreased in ex vivo perfused working hearts from MHC-ATGL mice (WT: 745±88, MHC-ATGL: 504±56 nmol per gram dry weight per min, mean±SEM, n=13-14, p<0.05) despite increased capacity for TG hydrolysis. Interestingly, reduced myocardial TG accumulation was associated with enhanced systolic function in MHC-ATGL mice (ejection fraction WT: 52.9±3.6, MHC-ATGL: 69.3±4.5%, mean±SEM, n=5, p<0.05), while parameters of diastolic function were unchanged. In addition, hearts from MHC-ATGL mice exhibited improved ex vivo performance when challenged with high workload. Most importantly and consistent with increased systolic function at baseline, MHC-ATGL mice were protected from pressure overload-induced systolic dysfunction and detrimental structural remodeling following transverse aortic constriction (ejection fraction at 5 weeks post transverse aortic constriction WT: 45.4±4.2, MHC-ATGL: 60.2±3.6%, mean±SEM, n=6-10, p<0.05; left ventricular internal diameter in systole WT: 3.3±0.1, MHC-ATGL: 2.6±0.2 mm, mean±SEM, n=6-10, p<0.01). Collectively, our study shows that cardiomyocyte-specific over-expression of a TG hydrolase can improve systolic function in the healthy heart as well as protect the heart from pressure overload-induced cardiac dysfunction. As such, we suggest that pharmacological modification of myocardial ATGL activity could be of therapeutic benefit in the diseased myocardium.
- © 2011 by American Heart Association, Inc.