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
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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DOI：
10.1128/mcb.01109-14
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发表时间：
2014-12
影响因子：
5.3
通讯作者：
A. Wende;Brian T. O’Neill;H. Bugger;C. Riehle;Joseph Tuinei;J. Buchanan;Kensuke Tsushima;Li Wang-
中科院分区：
文献类型：
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作者：
A. Wende;Brian T. O’Neill;H. Bugger;C. Riehle;Joseph Tuinei;J. Buchanan;Kensuke Tsushima;Li Wang-
摘要持续的Akt激活可诱导心脏肥大（LVH），从而可能导致心力衰竭。本研究验证了Akt激活导致病理性LVH中线粒体功能障碍的假设。Akt激活诱导LVH和线粒体脂肪酸氧化（FAO）途径的进行性抑制。通过抑制mTOR来预防LVH未能阻止线粒体功能的下降，但葡萄糖利用得以维持。Akt激活抑制体内线粒体调节基因、FAO和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，部分原因是减少FOXO介导的靶向Akt的核基因的转录激活，同时减少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传导。在培养的心肌细胞中，Akt激活破坏了线粒体生物能量学，这可以通过维持核FOXO而不是通过增加PGC-1α来部分逆转。因此，虽然短期Akt激活可通过减少线粒体代谢和增加糖酵解而在缺血期间具有心脏保护作用，但成人心脏中的长期Akt激活部分地通过减少线粒体氧化能力而促成病理性LVH。
ABSTRACT 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.