Roles of transcriptional corepressor RIP140 and coactivator PGC-1α in energy state of chronically infarcted rat hearts and mitochondrial function of cardiomyocytes

Transcriptional coactivator PPARγ coactivator-1α (PGC-1α) and corepressor receptor-interacting protein 140 (RIP140) are opposing-functional regulators in maintaining energy balance of most metabolic tissues and cells. However, the relative contributions of both factors to energy metabolism in cardiomyocytes remain largely unknown. Herein, we reported that the relative protein levels of RIP140/PGC-1α were up-regulated in the failing hearts after chronic myocardial infarction (MI), and correlated negatively with the energy state index phosphocreatine (PCr)/ATP ratios. Real-time PCR analysis revealed that mRNA expressions of estrogen related receptor α (ERRα), peroxisome proliferate activated receptor α and β (PPARα, PPARβ), nuclear respiratory factor 1 (NRF1) and their target genes were repressed by RIP140 and induced by PGC-1α in a dose dependent manner in neonatal rat cardiomyocytes. We also observed that overexpression of RIP140 through adenovirus delivery can abrogate the PGC-1α-mediated induction of mitochondrial membrane potential elevation and mitochondrial biogenesis, and activate both autophagy and apoptosis pathways. We conclude that RIP140 and PGC-1α exert antagonistic role in regulating cardiac energy state and mitochondrial biogenesis.

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► Relative protein levels of RIP140 to PGC-1α correlated negatively with PCr/ATP ratios in chronically infarcted rat hearts.
► RIP140 repressed the expression of genes involved in fatty acid and glucose metabolism.
► PGC-1α-induced mitochondrial biogenesis and elevation of membrane potential were reversed by RIP140 in dose dependent manner.
► Autophagy and apoptosis were inactivated by PGC-1α but induced by RIP140.