title: Roles of histone deacetylation and AMP kinase in regulation of cardiomyocyte PGC-1α gene expression in hypoxia.
abstract: The transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a key determinant of cardiac metabolic function by regulating genes governing fatty acid oxidation and mitochondrial biogenesis. PGC-1α expression is reduced in many cardiac diseases, and gene deletion of PGC-1α results in impaired cardiomyocyte metabolism and function. Reduced fuel supply generally induces PGC-1α expression, but the specific role of oxygen deprivation is unclear, and the mechanisms governing PGC-1α gene expression in these situations are poorly understood. During hypoxia of primary rat cardiomyocytes up to 12 h, we found that PGC-1α expression was downregulated via a histone deacetylation-dependent mechanism. Conversely, extended hypoxia to 24 h concomitant with glucose depletion upregulated PGC-1α expression via an AMP-activated protein kinase (AMPK)-mediated mechanism. Our previous work demonstrated that estrogen-related receptor-α (ERRα) regulates PGC-1α expression, and we show here that overexpression of ERRα was sufficient to attenuate PGC-1α downregulation in hypoxia. We confirmed that chronic hypoxia downregulated cardiac PGC-1α expression in a hypoxic but nonischemic hypobaric rat model of pulmonary hypertension. Our data demonstrate that depletion of oxygen or fuel results in repression or induction, respectively, of PGC-1α expression via discrete mechanisms, which may contribute to cardiac energetic derangement during hypoxia, ischemia, and failure.
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre and Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Angela
authors.initials: A
authors.lastname: Ramjiawan
authors.forename: Rushita A
authors.initials: RA
authors.lastname: Bagchi
authors.forename: Alexandra
authors.initials: A
authors.lastname: Blant
authors.forename: Laura
authors.initials: L
authors.lastname: Albak
authors.forename: Maria A
authors.initials: MA
authors.lastname: Cavasin
authors.forename: Todd R
authors.initials: TR
authors.lastname: Horn
authors.forename: Timothy A
authors.initials: TA
authors.lastname: McKinsey
authors.forename: Michael P
authors.initials: MP
authors.lastname: Czubryt
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000502:physiology*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D006657:Histones; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D000263:Adenylate Kinase; D006655:Histone Deacetylases
keywords: cardiomyocyte; energy metabolism; gene expression; hypoxia; transcription