Abstract 14989: SIRT3 Deficiency Impairs Mitochondrial and Contractile Function in the Heart
Sirtuin 3 (SIRT3) is a mitochondrial NAD+-dependent deacetylase which is highly expressed in the heart, and which increases mitochondrial ATP production. In rodent models of heart failure reduced SIRT3 expression is associated with mitochondrial dysfunction. Thus, we hypothesized that lack of SIRT3 may impair mitochondrial and contractile function in the heart. In isolated working hearts, developed pressure (-17%), cardiac power (-28%) and MVO2 (-17%) were significantly decreased in mice lacking SIRT3 (SIRT3-/-). Palmitate oxidation (-33%) and glucose oxidation (-39%) were decreased while rates of glycolysis (+40%; all p<0.05) were increased. In isolated mitochondria, respiratory capacity was reduced with glutamate (-16%), and was further reduced with palmitoyl-carnitine as substrate (-36%, each p<0.05). Similarly, ATP synthesis was reduced with palmitoyl-carnitine as substrate (-55%; p<0.05). HPLC measurements revealed a significantly decreased myocardial ATP/AMP ratio (-21%) and energy charge (-8%). Using GC-MS/MS analysis, SIRT3-/- hearts displayed significantly lower amounts of citrate but higher amounts of amino acids (K,Y,V,T,E) and 3-phosphoglycerate. In addition, hearts lacking SIRT3 showed increased amounts of malondialdehyde (+86%) and 4-hydroxynonenal (+68%; each p<0.05), indicative of oxidativ stress. Finally, SIRT3 deficiency resulted in a more pronounced decrease in ejection fraction (-18% vs. -27%; p<0.05) following 2 weeks of transverse aortic constriction, accompanied by an increased heart weight-tibia length ratio (9,3 vs. 13,1; p<0.05). Thus, lack of SIRT3 impairs mitochondrial and contractile function in the heart and accelerates the development of contractile dysfunction following aortic constriction, suggesting that reduced expression of SIRT3 in failing hearts may contribute to the development of cardiac dysfunction.
- © 2013 by American Heart Association, Inc.