Transcriptional corepressor RIP140 and coactivator PGC-1α regulate the cardiac energy state and mitochondrial biogenesis collectively

Yanfang Chen, Peiqing Liu. Department of Pharmacology and Toxicology,Pharmaceutical School, Sun Yat-sen University, Guangzhou,510006, China.

Transcriptional coactivator PPARγ coactivator-1α (PGC-1α) and corepressor receptor-interacting protein 140 (RIP140) are function-opposing regulators in maintaining energy balance of most metabolic tissues and cells (Hallberg et al., 2008). However, the relative contributions of both factors to energy metabolism in cardiomyocytes remain largely unknown.

In this study, we demonstrated a mild and severe cardiac dysfunction in infarcted non-failing and failing hearts after chronic myocardial infarction (MI), as previously described (Murray et al., 2008). Herein, we reported that the relative mRNA levels of RIP140 to PGC-1α were 3.98-fold higher in failing hearts compared with sham hearts (p<0.01). Linear correlation analysis displayed that the ratios of RIP140 to PGC-1α correlated negatively with energy state index phosphocreatine (PCr)/ATP ratio (r2 = 0.77, p<0.001), which was detected by HPLC analysis.

To test the relative contributions of these two factors in cardiomyocytes, primary cultures of cardiomyocytes were prepared from left ventricle of neonatal Sprague-Dawley rats according to the methods (Fu et al., 2005). We suggested that the expressions of estrogen related receptor α (ERRα), peroxisome proliferator activated receptor α and β (PPARα, PPARβ), and nuclear respiratory factor 1(NRF1) were repressed by overexpression of RIP140 through adenovirus delivery but induced by PGC-1α in neonatal rat cardiomyocytes. We also observed that cardiomyocytes treated with Ad-PGC-1α at MOI of 60 had a 60% increase in TMRE uptake versus control cells infected with Ad-GFP (p<0.001), whereas Ad-RIP140 dose-dependent loss of TMRE fluorescent was observed after different MOI of Ad-RIP140 infection. Results of mitochondrial morphology by transmission electron microscopy examination and copy numbers of mitochondrial DNA (mtDNA) by real-time RT-PCR analysis showed that RIP140 could abrogate the PGC-1α-mediated induction of mitochondrial biogenesis. In addition, the protein expression levels of LC3-II/LC3-I ratio and cleavage of caspase 3 were greatly increased along with the elevation expression of RIP140, suggesting the activation of both autophagy and apoptosis pathways. We conclude that RIP140 and PGC-1α exert antagonistic role in regulating the cardiac energy state and mitochondrial function.

Hallberg, M et al., 2008. Mol Cell Biol. 28, 6785-6795.

Murray, A.J et al., 2008. J Mol Cell Cardiol. 44, 694-700.

Fu, J.J et al., 2005. Cytotechnology. 49, 109-116.