AMPK inhibits cardiac hypertrophy by promoting autophagy via mTORC1
AMPK inhibits cardiac hypertrophy by promoting autophagy via mTORC1
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AMPK 通过 mTORC1 促进自噬抑制心脏肥大
DOI：
10.1016/j.abb.2014.06.023
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发表时间：
2014-09-15
影响因子：
3.9
通讯作者：
Dong, Yug
中科院分区：
文献类型：
--
作者：
Li, Yanh;Chen, Cong;Dong, Yug
AMPK是一种丝氨酸/苏氨酸蛋白激酶，是自噬的重要正向调节因子，是调控心肌肥大的关键因素。因此，我们探讨了AMPK是否通过调节自噬来抑制心肌肥厚。在压力超负荷所致的心肌肥厚中，检测到自噬减少。给予AMPK激动剂(AICAR和二甲双胍)显著阻止肥厚，伴随着心脏自噬水平的增强。此外，AMPK激活可促进自噬小体的形成，而不损害溶酶体的功能。体外研究表明，腺病毒过表达结构性激活的AMPK增加了自噬，并钝化了PE诱导的心肌细胞肥大。此外，我们还发现AICAR降低了mTORC1下游效应子4EBP1和p70S6K的磷酸化水平，但mTORC2下游信号AKT没有受到影响。此外，AMPK的激活不能对mTORC1抑制剂雷帕霉素诱导的自噬产生相加效应，表明AMPK通过抑制mTORC1而不是mTORC2来激活自噬。本研究证实AMPK通过mTORC1信号通路刺激自噬，从而抑制心肌肥厚。(C)2014 Elsevier Inc.保留所有权利。
AMPK, a serine/threonine protein kinase, has proven to be an important positive regulator of autophagy, which is a key factor in the regulation of cardiac hypertrophy. Thus, we explored whether AMPK could inhibit cardiac hypertrophy by regulating autophagy. In pressure overload induced cardiac hypertrophy, decreased autophagy was detected. Administration of AMPK activators (AICAR and metformin) significantly blocked hypertrophy, accompanied by enhanced autophagy level in the hearts. Furthermore, AMPK activation resulted in enhanced autophagosome formation and unimpaired lysosomal function. In vitro studies demonstrated adenoviral overexpression of constitutively activated AMPK increased autophagy and blunted PE-induced cardiomyocyte hypertrophy. Additionally, we found AICAR reduced the phosphorylation of the mTORC1 downstream effectors 4EBP1 and p70S6K, but AKT, which is a downstream signal of mTORC2, was not affected. Furthermore, activation by AMPK failed to lead to an additive effect on autophagy induced by the mTORC1 inhibitor rapamycin, indicating AMPK activates autophagy through the inhibition of mTORC1 but not of mTORC2. This study proved that AMPK can inhibit cardiac hypertrophy by stimulating autophagy through mTORC1 signaling. (C) 2014 Elsevier Inc. All rights reserved.