| First Author | Hu X | Year | 2011 |
| Journal | Hypertension | Volume | 58 |
| Issue | 4 | Pages | 696-703 |
| PubMed ID | 21825219 | Mgi Jnum | J:194448 |
| Mgi Id | MGI:5473777 | Doi | 10.1161/HYPERTENSIONAHA.111.174128 |
| Citation | Hu X, et al. (2011) AMP activated protein kinase-alpha2 regulates expression of estrogen-related receptor-alpha, a metabolic transcription factor related to heart failure development. Hypertension 58(4):696-703 |
| abstractText | 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-alpha (ERRalpha), but not peroxisome proliferator-activated receptor-gamma coactivator 1alpha, in human heart failure samples. In addition, chronic pressure overload in mice caused a decrease of ERRalpha 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 ERRalpha expression in vivo and in vitro. AMPKalpha2 knockout decreased myocardial ERRalpha (both mRNA and protein) and its downstream targets under basal conditions, with no change in myocardial peroxisome proliferator-activated receptor-gamma coactivator 1alpha expression. Using cultured rat neonatal cardiac myocytes, we found that overexpression of constitutively active AMPKalpha significantly induced ERRalpha mRNA, protein, and promoter activity. Conversely, selective gene silencing of AMPKalpha2 repressed ERRalpha and its target gene levels, indicating that AMPKalpha2 is involved in the regulation of ERRalpha expression. In addition, overexpression of ERRalpha in AMPKalpha2 knockout neonatal cardiac myocytes partially rescued the repressed expression of some energy metabolism-related genes. These data support an important role for AMPKalpha2 in regulating the expression of myocardial ERRalpha and its downstream mitochondrial enzymes. |
