期刊
PLOS ONE
卷 7, 期 10, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0046753
关键词
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资金
- Fondation de France [FDF_R08111LL]
- Universite Paris-Sud [IFR 141]
- LabEx LERMIT
Background: Mitochondrial function is dramatically altered in heart failure (HF). This is associated with a decrease in the expression of the transcriptional coactivator PGC-1 alpha, which plays a key role in the coordination of energy metabolism. Identification of compounds able to activate PGC-1 alpha transcription could be of future therapeutic significance. Methodology/Principal Findings: We thus developed a robotized cellular assay to screen molecules in order to identify new activators of PGC-1 alpha in a cardiac-like cell line. This screening assay was based on both the assessment of activity and gene expression of a secreted luciferase under the control of the human PGC-1 alpha promoter, stably expressed in H9c2 cells. We screened part of a library of human endogenous ligands and steroid hormones, B vitamins and fatty acids were identified as activators of PGC-1 alpha expression. The most responsive compounds of these families were then tested for PGC1-alpha gene expression in adult rat cardiomyocytes. These data highly confirmed the primary screening, and the increase in PGC-1 alpha mRNA correlated with an increase in several downstream markers of mitochondrial biogenesis. Moreover, respiration rates of H9c2 cells treated with these compounds were increased evidencing their effectiveness on mitochondrial biogenesis. Conclusions/Significance: Using our cellular reporter assay we could identify three original families, able to activate mitochondrial biogenesis both in cell line and adult cardiomyocytes. This first screening can be extended to chemical libraries in order to increase our knowledge on PGC-1 alpha regulation in the heart and to identify potential therapeutic compounds able to improve mitochondrial function in HF.
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