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  • PPARα-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway.

PPARα-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway.

Cell metabolism (2011-11-08)
Shinichi Oka, Ralph Alcendor, Peiyong Zhai, Ji Yeon Park, Dan Shao, Jaeyeaon Cho, Takanobu Yamamoto, Bin Tian, Junichi Sadoshima
ABSTRACT

High energy production in mitochondria is essential for maintaining cardiac contraction in the heart. Genes regulating mitochondrial function are commonly downregulated during heart failure. Here we show that both PPARα and Sirt1 are upregulated by pressure overload in the heart. Haploinsufficiency of either PPARα or Sirt1 attenuated pressure overload-induced cardiac hypertrophy and failure, whereas simultaneous upregulation of PPARα and Sirt1 exacerbated the cardiac dysfunction. PPARα and Sirt1 coordinately suppressed genes involved in mitochondrial function that are regulated by estrogen-related receptors (ERRs). PPARα bound and recruited Sirt1 to the ERR response element (ERRE), thereby suppressing ERR target genes in an RXR-independent manner. Downregulation of ERR target genes was also observed during fasting, and this appeared to be an adaptive response of the heart. These results suggest that suppression of the ERR transcriptional pathway by PPARα/Sirt1, a physiological fasting response, is involved in the progression of heart failure by promoting mitochondrial dysfunction.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Mitochondria Isolation Kit, sufficient for 10-20 g (animal tissue), sufficient for 50 assays (2 mL), isolation of enriched mitochondrial fraction from animal tissues