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Published on: September 25, 2017
Sestrin 1 ameliorates cardiac hypertrophy via autophagy activation
Ruicong Xue1,2, Junyi Zeng1,2, Yili Chen1,2
1Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
Insights
Sestrin 1 protein levels decrease in cardiac hypertrophy. Overexpressing Sestrin 1 inhibits cardiac hypertrophy by activating the AMPK/mTORC1/autophagy pathway, while its knockdown worsens the condition.
Area of Science:
- Cardiology
- Molecular Biology
- Cellular Biology
Background:
- Cardiac hypertrophy is a significant risk factor for cardiovascular diseases.
- Autophagy plays a crucial role in regulating cardiac hypertrophy.
- Sestrin 1, a p53 target gene, influences autophagy, but its role in cardiac hypertrophy is unclear.
Purpose of the Study:
- To investigate the role of Sestrin 1 in cardiac hypertrophy.
- To elucidate the underlying molecular mechanisms of Sestrin 1 in cardiac hypertrophy.
Main Methods:
- Assessed Sestrin 1 expression in pressure overload and phenylephrine-induced cardiac hypertrophy models.
- Utilized RNA interference (RNAi) to knockdown Sestrin 1 and adenovirus transfection for its overexpression.
- Examined autophagy flux and lysosomal function.
- Investigated the involvement of the AMPK/mTORC1 signaling pathway.
Main Results:
- Sestrin 1 expression was reduced in cardiac hypertrophy.
- Sestrin 1 knockdown exacerbated hypertrophy, while overexpression attenuated it.
- Sestrin 1 modulated autophagy, with overexpression enhancing it.
- The protective effect of Sestrin 1 was dependent on autophagy.
- Sestrin 1 interacts with AMPK to regulate the AMPK/mTORC1/autophagy pathway.
Conclusions:
- Sestrin 1 acts as a negative regulator of cardiac hypertrophy.
- Sestrin 1 attenuates cardiac hypertrophy by activating the AMPK/mTORC1/autophagy axis.
Abstract:
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.
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