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 (ERRα) plays an important role in regulating myocardial energy metabolism related genes and the adaption to stress. However, regulation of ERRαexpression 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 AMPKα1 and AMPKα2 in the regulation of ERRαexpression in both heart and isolated cardiac myocytes. Using cultured rat neonatal cardiac myocytes, we found that over-expression of constitutively active AMPKα2 or activation of AMPK by AICAR or metformin significantly increased ERRαmRNA, protein levels and promoter activity. The induction of ERRαby AICAR or metformin was blunted by selective gene silencing of AMPKα2, indicating that the activation of AMPKα2 is required for the induction of ERRα. In addition, by using global AMPKα1 and AMPKα2 gene deficient mice, we demonstrated that global AMPKα2 gene deficiency (KO) severely exacerbated LV hypertrophy and dysfunction in response to chronic systolic overload produced by transverse aortic constriction (TAC). AMPKá2 KO decreased myocardial ERRá (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 AMPKá1 KO had no effect on LV structure and function and myocardial ERRá content under control conditions or after chronic TAC, indicating that AMPKá1 does not play a significant role in myocardial ERRá expression and the development of CHF. Interestingly, overexpression of ERRá in AMPKá2 KO neonatal cardiac myocytes partially rescued the repressed expression of some energy metabolism related genes. Collectively, these data support an important role of AMPKá2, but not in AMPKá1, in regulating the expression of ERRá 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.