Abstract 3637: AMP Activated Protein Kinase Regulates the Expression of ERRalpha in Cardiac Myocytes

Maintaining myocardial mitochondrial enzyme expression is essential for preserving cardiac function during stress. Recent studies have demonstrated Estrogen-Related Receptor alpha (ERR α ) plays an important role in regulating myocardial energy metabolism related genes and the adaption to stress. However, regulation of ERR α expression in cardiac myocytes has not been well defined. In skeletal muscle, the metabolic sensor AMP activated protein kinase (AMPK) regulates expression of energy metabolism related genes. In the present study, we examined the functions of AMPK α 1 and AMPK α 2 in the regulation of ERR α expression in both heart and isolated cardiac myocytes. Using cultured rat neonatal cardiac myocytes, we found that over-expression of constitutively active AMPK α 2 or activation of AMPK by AICAR or metformin significantly increased ERR α mRNA, protein levels and promoter activity. The induction of ERR α by AICAR or metformin was blunted by selective gene silencing of AMPK α 2, indicating that the activation of AMPK α 2 is required for the induction of ERR α . In addition, by using global AMPK α 1 and AMPK α 2 gene deficient mice, we demonstrated that global AMPK α 2 gene deficiency (KO) severely exacerbated LV hypertrophy and dysfunction in response to chronic systolic overload produced by transverse aortic constriction (TAC). AMPKa2 KO decreased myocardial ERRa (both mRNA and protein levels) and its downstream targets at baseline and resulted in further decreases of these genes after chronic TAC. In contrast, global AMPKa1 KO had no effect on LV structure and function and myocardial ERRa content under control conditions or after chronic TAC, indicating that AMPKa1 does not play a significant role in myocardial ERRa expression and the development of CHF. Interestingly, overexpression of ERRa in AMPKa2 KO neonatal cardiac myocytes partially rescued the repressed expression of some energy metabolism related genes. Collectively, these data support an important role of AMPKa2, but not in AMPKa1, in regulating the expression of ERRa and its downstream energy metabolic enzymes in heart and in isolated cardiac myocytes; and in protection heart against systolic overload induced ventricular hypertrophy and heart failure.