Sestrin 1 ameliorates cardiac hypertrophy via autophagy activation.

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.

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。