Abstract 13696: Cardiac-specific Overexpression of Bdh1 Ameliorates Oxidative Stress and Cardiac Remodeling in Pressure Overload Heart Failure
Background: The shift of energy substrate from fatty acid to glucose accompanied by myocardial energy compromise is the hallmark of metabolic remodeling in pathological cardiac hypertrophy. However, it has not been investigated the pathological involvement of ketone body metabolism in heart failure.
Methods and results: Pressure overload heart failure was introduced with the transverse aortic constriction (TAC) and samples were obtained 8 weeks after operation. Microarray and mitochondrial iTRAQ proteome revealed that the expression of Bdh1, an enzyme that catalyzes the NAD+/NADH coupled interconversion of acetoacetate and beta-hydroxybutyrate (betaOHB), was increased 2.5-fold and 2.8-fold in TAC-operated heart, respectively. Consistent with these results, ketone body oxidation determined by measuring 14CO2 released from the metabolism of [1-14C][[Unable to Display Character: ]]betaOHB in isolated perfused hearts was upregulated 1.8-fold in TAC-operated heart. To investigate the functional significance of upregulated ketone body oxidation, we generated heart-specific Bdh1 Tg mice to recapitulate the increases in basal ketone body oxidation observed in hypertrophied hearts. Bdh1 Tg mice had 1.7-fold increase of ketone body oxidation in the heart and did not exhibit any differences in baseline characteristics. When subjected to TAC operation, Bdh1 Tg mice were resistant to cardiac hypertrophy, contractile dysfunction, fibrosis and mitochondrial damage. Immunochemical detection of carbonylated proteins demonstrated that protein oxidative damage was ameliorated in Bdh1 Tg mice. Continuously we performed in vitro study using rat neonatal cardiomyocytes. Angiotensin II-induced ROS production in cardiomyocytes was decreased by adenovirus-mediated Bdh1 overexpression. Hydrogen peroxide-induced apoptosis was also attenuated by Bdh1 overexpression.
Conclusions: Present study demonstrated that ketone body oxidation was promoted in hypertrophied hearts. Increasing ketone body utilization reduced oxidative stress and protected against heart failure progression after chronic pressure overload.
- © 2013 by American Heart Association, Inc.