Sirtuin 3 Alleviates Diabetic Cardiomyopathy by Regulating TIGAR and Cardiomyocyte Metabolism

Abstract

Background Impairment of glycolytic metabolism is suggested to contribute to diabetic cardiomyopathy. In this study, we explored the roles of SIRT3 (Sirtuin 3) on cardiomyocyte glucose metabolism and cardiac function. Methods and Results Exposure of H9c2 cardiomyocyte cell lines to high glucose (HG) (30 mmol/L) resulted in a gradual decrease in SIRT3 and 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase isoform 3 (PFKFB3) expression together with increases in p53 acetylation and TP53‐induced glycolysis and apoptosis regulator (TIGAR) expression. Glycolysis was significantly reduced in the cardiomyocyte exposed to HG. Transfection with adenovirus‐SIRT3 significantly increased PFKFB3 expression and reduced HG‐induced p53 acetylation and TIGAR expression. Overexpression of SIRT3 rescued impaired glycolysis and attenuated HG–induced reactive oxygen species formation and apoptosis. Knockdown of TIGAR in cardiomyocytes by using siRNA significantly increased PFKFB3 expression and glycolysis under hyperglycemic conditions. This was accompanied by a significant suppression of HG–induced reactive oxygen species formation and apoptosis. In vivo, overexpression of SIRT3 by an intravenous jugular vein injection of adenovirus‐SIRT3 resulted in a significant reduction of p53 acetylation and TIGAR expression together with upregulation of PFKFB3 expression in the heart of diabetic db/db mice at day 14. Overexpression of SIRT3 further reduced reactive oxygen species formation and blunted microvascular rarefaction in the diabetic db/db mouse hearts. Overexpression of SIRT3 significantly blunted cardiac fibrosis and hypertrophy and improved cardiac function at day 14. Conclusions Our study demonstrated that SIRT3 attenuated diabetic cardiomyopathy via regulating p53 acetylation and TIGAR expression. Therefore, SIRT3 may be a novel target for abnormal energy metabolism in diabetes mellitus.

Keywords

• diabetic cardiomyopathy
• glycolysis
• p53 acetylation
• Sirtuin 3
• TP53‐induced glycolysis and apoptosis regulator