Heart AMP Activated Protein Kinase- 2 Regulates Expression of Estrogen-Related Receptor- , a Metabolic Transcription Factor Related to Heart Failure Development

The normal expression of myocardial mitochondrial enzymes is essential to maintain the cardiac energy reserve and facilitate responses to stress, but the molecular mechanisms to maintain myocardial mitochondrial enzyme expression have been elusive. Here we report that congestive heart failure is associated with a significant decrease of myocardial estrogen-related receptor(ERR ), but not peroxisome proliferator-activated receptorcoactivator 1 , in human heart failure samples. In addition, chronic pressure overload in mice caused a decrease of ERR expression that was significantly correlated to the degree of left ventricular dysfunction, pulmonary congestion, and decreases of a group of myocardial energy metabolism–related genes. We found that the metabolic sensor AMP activated protein kinase (AMPK) regulates ERR expression in vivo and in vitro. AMPK 2 knockout decreased myocardial ERR (both mRNA and protein) and its downstream targets under basal conditions, with no change in myocardial peroxisome proliferator-activated receptorcoactivator 1 expression. Using cultured rat neonatal cardiac myocytes, we found that overexpression of constitutively active AMPK significantly induced ERR mRNA, protein, and promoter activity. Conversely, selective gene silencing of AMPK 2 repressed ERR and its target gene levels, indicating that AMPK 2 is involved in the regulation of ERR expression. In addition, overexpression of ERR in AMPK 2 knockout neonatal cardiac myocytes partially rescued the repressed expression of some energy metabolism-related genes. These data support an important role for AMPK 2 in regulating the expression of myocardial ERR and its downstream mitochondrial enzymes. (Hypertension. 2011;58:696-703.) ● Online Data Supplement