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Substrate metabolism regulated by Sestrin2-mTORC1 alleviates pressure overload-induced cardiac hypertrophy in aged heart.

ABSTRACT: Sestrin2 (Sesn2) is a stress sensor for the mammalian target of rapamycin complex 1 (mTORC1) pathway. Aging impairs cardiac mTORC1 activation, thereby sensitizing the heart to hypertrophy. C57BL/6 J young wild-type (young WT; 4-6 months), aged WT (24-26 months), and young Sestrin2 knockout mice (Y-Sesn2 KO; 4-6 months) underwent transverse aortic constriction (TAC) for pressure overload. Cardiac expression of Sesn2 decreased with age. At 4 weeks after TAC, aged WT and Y-Sesn2 KO exhibited larger hearts and impaired cardiac function, compared with young WT mice. Augmented phosphorylation of mTOR and downstream effectors; damaged mitochondria and elevated redox markers, as well as and impaired glucose and fatty acid oxidation were observed in aged WT and Y-Sesn2 KO hearts. A pressure overload-induced interaction between Sesn2 and GTPase-activating protein activity toward Rags 2 (GATOR2), which positively regulates mTORC1, was impaired in aged WT hearts. Adeno-associated virus 9-Sesn2 treatment rescued Sesn2 expression, attenuated mTORC1 activation, and increased pressure overload tolerance in aged WT and Y-Sesn2 KO hearts. These results indicated that cardiac Sesn2 acts as a pressure overload sensor for mTORC1. Furthermore, Sesn2 deficiency may cause increased sensitivity to hypertrophy in elderly individuals.

SUBMITTER: Quan N

PROVIDER: S-EPMC7363709 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Substrate metabolism regulated by Sestrin2-mTORC1 alleviates pressure overload-induced cardiac hypertrophy in aged heart.

Quan Nanhu N Li Xuan X Zhang Jingwen J Han Ying Y Sun Weiju W Ren Di D Tong Qian Q Li Ji J

Redox biology 20200709

Sestrin2 (Sesn2) is a stress sensor for the mammalian target of rapamycin complex 1 (mTORC1) pathway. Aging impairs cardiac mTORC1 activation, thereby sensitizing the heart to hypertrophy. C57BL/6 J young wild-type (young WT; 4-6 months), aged WT (24-26 months), and young Sestrin2 knockout mice (Y-Sesn2 KO; 4-6 months) underwent transverse aortic constriction (TAC) for pressure overload. Cardiac expression of Sesn2 decreased with age. At 4 weeks after TAC, aged WT and Y-Sesn2 KO exhibited larger ...[more]

PMID: 32863202

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Project description:Objectives: Sestrin2 (Sesn2) has been demonstrated to be a cysteine sulfinyl reductase and protects cells from multiple stress insults, including hypoxia, endoplasmic reticulum stress, and oxidative stress. However, the roles and mechanisms of Sesn2 in pressure overload-induced mouse cardiac hypertrophy have not been clearly clarified. This study intended to investigate whether sestrin2 (Sesn2) overexpression could prevent pressure overload-induced cardiac hypertrophy via an AMPKα2 dependent pathway through conditional knockout of AMPKα2. Methods and results: Sesn2 expression was significantly increased in mice hearts at 2 and 4 weeks after aortic banding (AB) surgery, but decreased to 60-70% of the baseline at 8 weeks. Sesn2 overexpression (at 3, 6, and 9 folds) showed little cardiac genetic toxicity in transgenic mice. Cardiac dysfunctions induced by pressure overload were attenuated by cardiomyocyte-specific Sesn2 overexpression when measured by echocardiography and hemodynamic analysis. Results of HE and PSR staining showed that Sesn2 overexpression significantly alleviated cardiac hypertrophy and fibrosis in mice hearts induced by pressure overload. Meanwhile, adenovirus-mediated-Sesn2 overexpression markedly suppressed angiotensin II-induced neonatal rat cardiomyocyte hypertrophy in vitro. Mechanistically, Sesn2 overexpression increased AMPKα2 phosphorylation but inhibited mTORC1 phosphorylation. The cardiac protections of Sesn2 overexpression were also via regulating oxidative stress by enhancing Nrf2/HO-1 signaling, restoring SOD activity, and suppressing NADPH activity. Particularly, we first proved the vital role of AMPKα2 in the regulation of Sesn2 with AMPKα2 knockout (AMPKα2-/-) mice and Sesn2 transgenic mice crossed with AMPKα2-/-, since Sesn2 overexpression failed to improve cardiac function, inhibit cardiac hypertrophy and fibrosis, and attenuate oxidative stress after AMPKα2 knockout. Conclusion: This study uniquely revealed that Sesn2 overexpression showed little genetic toxicity in mice hearts and inhibited mTORC1 activation and oxidative stress to protect against pressure overload-induced cardiac hypertrophy in an AMPKα2 dependent pathway. Thus, interventions through promoting Sesn2 expression might be a potential strategy for treating pathological cardiac hypertrophy and heart failure.

Dataset Information

Substrate metabolism regulated by Sestrin2-mTORC1 alleviates pressure overload-induced cardiac hypertrophy in aged heart.

Publications

Substrate metabolism regulated by Sestrin2-mTORC1 alleviates pressure overload-induced cardiac hypertrophy in aged heart.

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