Roles of histone deacetylation and AMP kinase in regulation of cardiomyocyte PGC-1α gene expression in hypoxia

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) is a key determinant of cardiac metabolic function by regulating genes governing fatty acid oxidation and mitochondrial biogenesis. PGC-1 alpha expression is reduced in many cardiac diseases, and gene deletion of PGC-1 alpha results in impaired cardiomyocyte metabolism and function. Reduced fuel supply generally induces PGC-1 alpha expression, but the specific role of oxygen deprivation is unclear, and the mechanisms governing PGC-1 alpha gene expression in these situations are poorly understood. During hypoxia of primary rat cardiomyocytes up to 12 h, we found that PGC-1 alpha expression was downregulated via a histone deacetylation-dependent mechanism. Conversely, extended hypoxia to 24 h concomitant with glucose depletion upregulated PGC-1 alpha expression via an AMP-activated protein kinase (AMPK)-mediated mechanism. Our previous work demonstrated that estrogen-related receptor-alpha (ERR alpha) regulates PGC-1 alpha expression, and we show here that overexpression of ERR alpha was sufficient to attenuate PGC-1 alpha downregulation in hypoxia. We confirmed that chronic hypoxia downregulated cardiac PGC-1 alpha 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-1 alpha expression via discrete mechanisms, which may contribute to cardiac energetic derangement during hypoxia, ischemia, and failure.