Knockout of AMPKα2 Blocked the Protection of Sestrin2 Overexpression Against Cardiac Hypertrophy Induced by Pressure Overload
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 hypertr...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:f50d65d73ef8430e9d5b093ff50588cb2021-11-17T06:30:39ZKnockout of AMPKα2 Blocked the Protection of Sestrin2 Overexpression Against Cardiac Hypertrophy Induced by Pressure Overload1663-981210.3389/fphar.2021.716884https://doaj.org/article/f50d65d73ef8430e9d5b093ff50588cb2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.716884/fullhttps://doaj.org/toc/1663-9812Objectives: 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.Nan ZhangNan ZhangNan ZhangHai-Han LiaoHai-Han LiaoHai-Han LiaoHong FengShan-Qi MouShan-Qi MouShan-Qi MouWen-Jing LiWen-Jing LiWen-Jing LiXiahenazi AiyasidingXiahenazi AiyasidingXiahenazi AiyasidingZheng LinZheng LinZheng LinWen DingWen DingWen DingZi-Ying ZhouZi-Ying ZhouZi-Ying ZhouHan YanSi ChenSi ChenQi-Zhu TangQi-Zhu TangQi-Zhu TangFrontiers Media S.A.articleSestrin2cardiac hypertrophyfibrosisAMPKαoxidative stressTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021) |
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| topic |
Sestrin2 cardiac hypertrophy fibrosis AMPKα oxidative stress Therapeutics. Pharmacology RM1-950 |
| spellingShingle |
Sestrin2 cardiac hypertrophy fibrosis AMPKα oxidative stress Therapeutics. Pharmacology RM1-950 Nan Zhang Nan Zhang Nan Zhang Hai-Han Liao Hai-Han Liao Hai-Han Liao Hong Feng Shan-Qi Mou Shan-Qi Mou Shan-Qi Mou Wen-Jing Li Wen-Jing Li Wen-Jing Li Xiahenazi Aiyasiding Xiahenazi Aiyasiding Xiahenazi Aiyasiding Zheng Lin Zheng Lin Zheng Lin Wen Ding Wen Ding Wen Ding Zi-Ying Zhou Zi-Ying Zhou Zi-Ying Zhou Han Yan Si Chen Si Chen Qi-Zhu Tang Qi-Zhu Tang Qi-Zhu Tang Knockout of AMPKα2 Blocked the Protection of Sestrin2 Overexpression Against Cardiac Hypertrophy Induced by Pressure Overload |
| 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. |
| format |
article |
| author |
Nan Zhang Nan Zhang Nan Zhang Hai-Han Liao Hai-Han Liao Hai-Han Liao Hong Feng Shan-Qi Mou Shan-Qi Mou Shan-Qi Mou Wen-Jing Li Wen-Jing Li Wen-Jing Li Xiahenazi Aiyasiding Xiahenazi Aiyasiding Xiahenazi Aiyasiding Zheng Lin Zheng Lin Zheng Lin Wen Ding Wen Ding Wen Ding Zi-Ying Zhou Zi-Ying Zhou Zi-Ying Zhou Han Yan Si Chen Si Chen Qi-Zhu Tang Qi-Zhu Tang Qi-Zhu Tang |
| author_facet |
Nan Zhang Nan Zhang Nan Zhang Hai-Han Liao Hai-Han Liao Hai-Han Liao Hong Feng Shan-Qi Mou Shan-Qi Mou Shan-Qi Mou Wen-Jing Li Wen-Jing Li Wen-Jing Li Xiahenazi Aiyasiding Xiahenazi Aiyasiding Xiahenazi Aiyasiding Zheng Lin Zheng Lin Zheng Lin Wen Ding Wen Ding Wen Ding Zi-Ying Zhou Zi-Ying Zhou Zi-Ying Zhou Han Yan Si Chen Si Chen Qi-Zhu Tang Qi-Zhu Tang Qi-Zhu Tang |
| author_sort |
Nan Zhang |
| title |
Knockout of AMPKα2 Blocked the Protection of Sestrin2 Overexpression Against Cardiac Hypertrophy Induced by Pressure Overload |
| title_short |
Knockout of AMPKα2 Blocked the Protection of Sestrin2 Overexpression Against Cardiac Hypertrophy Induced by Pressure Overload |
| title_full |
Knockout of AMPKα2 Blocked the Protection of Sestrin2 Overexpression Against Cardiac Hypertrophy Induced by Pressure Overload |
| title_fullStr |
Knockout of AMPKα2 Blocked the Protection of Sestrin2 Overexpression Against Cardiac Hypertrophy Induced by Pressure Overload |
| title_full_unstemmed |
Knockout of AMPKα2 Blocked the Protection of Sestrin2 Overexpression Against Cardiac Hypertrophy Induced by Pressure Overload |
| title_sort |
knockout of ampkα2 blocked the protection of sestrin2 overexpression against cardiac hypertrophy induced by pressure overload |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/f50d65d73ef8430e9d5b093ff50588cb |
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