title: AMP activated protein kinase-α2 regulates expression of estrogen-related receptor-α, a metabolic transcription factor related to heart failure development.
abstract: 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-α (ERRα), but not peroxisome proliferator-activated receptor-γ coactivator 1α, in human heart failure samples. In addition, chronic pressure overload in mice caused a decrease of ERRα 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 ERRα expression in vivo and in vitro. AMPKα2 knockout decreased myocardial ERRα (both mRNA and protein) and its downstream targets under basal conditions, with no change in myocardial peroxisome proliferator-activated receptor-γ coactivator 1α expression. Using cultured rat neonatal cardiac myocytes, we found that overexpression of constitutively active AMPKα significantly induced ERRα mRNA, protein, and promoter activity. Conversely, selective gene silencing of AMPKα2 repressed ERRα and its target gene levels, indicating that AMPKα2 is involved in the regulation of ERRα expression. In addition, overexpression of ERRα in AMPKα2 knockout neonatal cardiac myocytes partially rescued the repressed expression of some energy metabolism-related genes. These data support an important role for AMPKα2 in regulating the expression of myocardial ERRα and its downstream mitochondrial enzymes.
authors.affiliation: Cardiovascular Division, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Xinli
authors.initials: X
authors.lastname: Hu
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Zhongbing
authors.initials: Z
authors.lastname: Lu
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: John
authors.initials: J
authors.lastname: Fassett
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Xin
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hall
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bache
authors.forename: Yimin
authors.initials: Y
authors.lastname: Huang
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Chen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology; D005260:Female; D006333:Heart Failure / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000201:enzymology; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000503:physiopathology; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D055372:AMP-Activated Protein Kinases; D006360:Heat-Shock Proteins; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011960:Receptors, Estrogen; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor; C486497:PPARGC1A protein, human; C534978:Prkaa2 protein, mouse