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首页> 外文期刊>Cell metabolism >PPARalpha-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway.
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PPARalpha-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway.

机译：PPARalpha-Sirt1复合体通过抑制ERR转录途径介导心脏肥大和衰竭。

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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 PPARalpha and Sirt1 are upregulated by pressure overload in the heart. Haploinsufficiency of either PPARalpha or Sirt1 attenuated pressure overload-induced cardiac hypertrophy and failure, whereas simultaneous upregulation of PPARalpha and Sirt1 exacerbated the cardiac dysfunction. PPARalpha and Sirt1 coordinately suppressed genes involved in mitochondrial function that are regulated by estrogen-related receptors (ERRs). PPARalpha 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 PPARalpha/Sirt1, a physiological fasting response, is involved in the progression of heart failure by promoting mitochondrial dysfunction.
机译：线粒体的高能量产生对于维持心脏的心脏收缩至关重要。心力衰竭期间，调节​​线粒体功能的基因通常被下调。在这里，我们显示PPARalpha和Sirt1都被心脏压力超负荷上调。 PPARalpha或Sirt1的单倍剂量不足会减轻压力超负荷引起的心脏肥大和衰竭，而PPARalpha和Sirt1的同时上调则加剧了心脏功能障碍。 PPARalpha和Sirt1协同抑制由雌激素相关受体（ERRs）调控的线粒体功能基因。 PPARalpha将Sirt1结合并募集到ERR反应元件（ERRE），从而以独立于RXR的方式抑制ERR目标基因。禁食期间也观察到ERR靶基因的下调，这似乎是心脏的适应性反应。这些结果表明，PPARalpha / Sirt1对ERR转录途径的抑制（一种生理上的禁食反应）通过促进线粒体功能障碍而参与了心力衰竭的进展。

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