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: Angela Ramjiawan, Rushita A Bagchi, Alexandra Blant, Laura Albak, Maria A Cavasin, Todd R Horn, Timothy A McKinsey, Michael P Czubryt
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 304 Issue 11 Pg. C1064-72 (Jun 01 2013) ISSN: 1522-1563 [Electronic] United States
• PMID: 23515531 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histones
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Ppargc1a protein, rat
• RNA-Binding Proteins
• Transcription Factors
• Adenylate Kinase
• Histone Deacetylases

Topics

• Adenylate Kinase (metabolism)
• Animals
• Chromatin Immunoprecipitation
• Disease Models, Animal
• Gene Expression Regulation (physiology)
• Histone Deacetylases (metabolism)
• Histones (metabolism)
• Hypertension, Pulmonary (genetics, metabolism)
• Hypoxia (genetics, metabolism)
• Myocytes, Cardiac (metabolism)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• RNA-Binding Proteins (biosynthesis, genetics)
• Rats
• Real-Time Polymerase Chain Reaction
• Transcription Factors (biosynthesis, genetics)