Abstract
Cardiac hypertrophy is an adaptive response to pressure, volume stress, and loss of contractile mass from prior infarction. Metabolic changes in cardiac hypertrophy include suppression of fatty acid oxidation and enhancement of glucose utilization, which could result in lipid accumulation in the heart. SIRT3, a mitochondrial NAD+-dependent deacetylase, has been demonstrated to play a crucial role in controlling the acetylation status of many enzymes participating in energy metabolism. However, the role of SIRT3 in the pathogenesis of hypertrophy-related lipid accumulation remains unclear. In this study, hypertrophy-related lipid accumulation was investigated using a mouse cardiac hypertrophy model induced by transverse aortic constriction (TAC). We showed that mice developed heart failure six weeks after TAC. Furthermore, abnormal lipid accumulation and decreased palmitate oxidation rates were observed in the hypertrophic hearts, and these changes were particularly significant in SIRT3-KO mice. We also demonstrated that the short form of SIRT3 was downregulated in wild-type (WT) hypertrophic hearts and that this change was accompanied by a higher acetylation level of long-chain acyl CoA dehydrogenase (LCAD), which is a key enzyme participating in fatty acid oxidation. In addition, SIRT3 may play an essential role in attenuating lipid accumulation in the heart through the deacetylation of LCAD.
Highlights
Cardiac hypertrophy is an adaptive response that is accompanied by many forms of heart disease, including ischemic disease, hypertension, heart failure, and valvular disease [1,2,3]
The mice subjected to transverse aortic constriction (TAC) produced nearly 20%, 40%, and 60% cardiac hypertrophy, respectively, two, four, and six weeks after TAC (Fig. 1C), and we found that the short form of SIRT3 was downregulated after TAC compared with the sham controls (Fig. 1D and 1F), whereas the long form was slightly increased during mild hypertrophy but did not show obvious changes during severe hypertrophy (Fig. 1D and 1E)
It was shown that the short form of SIRT3 was downregulated during hypertrophy in WT mice, and this effect was accompanied by a higher acetylation level of long-chain acyl CoA dehydrogenase (LCAD)
Summary
Cardiac hypertrophy is an adaptive response that is accompanied by many forms of heart disease, including ischemic disease, hypertension, heart failure, and valvular disease [1,2,3]. It is important to suppress hypertrophy without provoking circulatory insufficiency.
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