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首页> 外文期刊>Molecular and Cellular Biology >Enhanced Cardiac Akt/Protein Kinase B Signaling Contributes to Pathological Cardiac Hypertrophy in Part by Impairing Mitochondrial Function via Transcriptional Repression of Mitochondrion-Targeted Nuclear Genes
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Enhanced Cardiac Akt/Protein Kinase B Signaling Contributes to Pathological Cardiac Hypertrophy in Part by Impairing Mitochondrial Function via Transcriptional Repression of Mitochondrion-Targeted Nuclear Genes

机译：增强的心脏Akt /蛋白激酶B信号转导部分通过通过线粒体靶向核基因的转录抑制来破坏线粒体功能，从而导致病理性心肌肥大。

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Sustained Akt activation induces cardiac hypertrophy (LVH), which may lead to heart failure. This study tested the hypothesis that Akt activation contributes to mitochondrial dysfunction in pathological LVH. Akt activation induced LVH and progressive repression of mitochondrial fatty acid oxidation (FAO) pathways. Preventing LVH by inhibiting mTOR failed to prevent the decline in mitochondrial function, but glucose utilization was maintained. Akt activation represses expression of mitochondrial regulatory, FAO, and oxidative phosphorylation genes in vivo that correlate with the duration of Akt activation in part by reducing FOXO-mediated transcriptional activation of mitochondrion-targeted nuclear genes in concert with reduced signaling via peroxisome proliferator-activated receptor α (PPARα)/PGC-1α and other transcriptional regulators. In cultured myocytes, Akt activation disrupted mitochondrial bioenergetics, which could be partially reversed by maintaining nuclear FOXO but not by increasing PGC-1α. Thus, although short-term Akt activation may be cardioprotective during ischemia by reducing mitochondrial metabolism and increasing glycolysis, long-term Akt activation in the adult heart contributes to pathological LVH in part by reducing mitochondrial oxidative capacity.
机译：持续的Akt激活会诱发心脏肥大（LVH），这可能导致心力衰竭。这项研究检验了Akt激活导致病理性LVH的线粒体功能障碍的假说。 Akt激活诱导LVH和线粒体脂肪酸氧化（FAO）途径的逐步抑制。通过抑制mTOR来预防LVH未能阻止线粒体功能下降，但维持了葡萄糖利用率。 Akt激活抑制线粒体调控基因，FAO和体内氧化磷酸化基因的表达，这些基因与Akt激活的持续时间相关，部分原因是通过减少FOXO介导的线粒体靶向核基因的转录激活以及降低过氧化物酶体增殖物激活受体α（PPARα）/PGC-1α和其他转录调节因子的信号转导。在培养的心肌细胞中，Akt激活破坏了线粒体的生物能，可以通过维持核FOXO而不是通过增加PGC-1α来部分逆转。因此，尽管短期Akt激活可能在缺血期间通过减少线粒体代谢和增加糖酵解而具有心脏保护作用，但成年心脏中的长期Akt激活部分地通过降低线粒体的氧化能力而有助于病理性LVH。

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