Sestrin 1 ameliorates cardiac hypertrophy via autophagy activation.
Sestrin 1 ameliorates cardiac hypertrophy via autophagy activation.
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Sestrin 1 通过自噬激活改善心脏肥大
DOI：
10.1111/jcmm.13052
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发表时间：
2017-06
影响因子：
5.3
通讯作者：
Liu C
中科院分区：
文献类型：
--
作者：
Xue R;Zeng J;Chen Y;Chen C;Tan W;Zhao J;Dong B;Sun Y;Dong Y;Liu C
心肌肥大是心血管疾病发病率和死亡率的主要危险因素之一。自噬被认为是调节心肌肥大的重要机制。Sestrin 1是p53的下游靶基因，已被证明可调节自噬。然而，Sestrin 1在心肌肥大中的作用仍不清楚。我们的研究表明，在压力超负荷性心肌肥大和苯肾上腺素（PE）诱导的心肌肥大中，Sestrin 1的mRNA和蛋白质表达下降。通过RNA干扰敲低Sestrin 1会加重PE诱导的心肌肥大，而通过腺病毒转染过表达Sestrin 1则会减轻肥大。我们发现敲低Sestrin 1会导致自噬受损，而过表达Sestrin 1会导致自噬增加且不影响溶酶体功能。此外，自噬阻断消除了Sestrin 1过表达的抗肥大作用。重要的是，Sestrin 1通过与负责自噬调节的AMPK相互作用，靶向AMPK/mTORC1/自噬途径来抑制心肌肥大。综上所述，我们的数据表明Sestrin 1调节AMPK/mTORC1/自噬轴以减轻心肌肥大。
Cardiac hypertrophy is one of the major risk factors of cardiovascular morbidity and mortality. Autophagy is acknowledged to be an important mechanism regulating cardiac hypertrophy. Sestrin 1, a downstream target gene of p53, has been proven to regulate autophagy. However, the role of Sestrin 1 in cardiac hypertrophy remains unknown. Our study showed that Sestrin 1 mRNA and protein expression declined in pressure overload cardiac hypertrophy and phenylephrine (PE)‐induced cardiac hypertrophy. Knockdown of Sestrin 1 by RNAi deteriorated PE‐induced cardiac hypertrophy, whereas the overexpression of Sestrin 1 by adenovirus transfection blunted hypertrophy. We discovered that knockdown of Sestrin 1 resulted in impaired autophagy while overexpression of Sestrin 1 resulted in increased autophagy without affecting lysosomal function. In addition, the antihypertrophic effect of Sestrin 1 overexpression was eliminated by autophagy blockade. Importantly, Sestrin 1 targets at the AMPK/mTORC1/autophagy pathway to inhibit cardiac hypertrophy by interaction with AMPK which is responsible for autophagy regulation. Taken together, our data indicate that Sestrin 1 regulates AMPK/mTORC1/autophagy axis to attenuate cardiac hypertrophy.