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.
2021-11-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.716884/full |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-19T00:02:33Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-19T00:02:33Z |
| publishDate | 2021-11-01 |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-f50d65d73ef8430e9d5b093ff50588cb2022-12-21T20:46:24ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-11-011210.3389/fphar.2021.716884716884Knockout of AMPKα2 Blocked the Protection of Sestrin2 Overexpression Against Cardiac Hypertrophy Induced by Pressure OverloadNan Zhang0Nan Zhang1Nan Zhang2Hai-Han Liao3Hai-Han Liao4Hai-Han Liao5Hong Feng6Shan-Qi Mou7Shan-Qi Mou8Shan-Qi Mou9Wen-Jing Li10Wen-Jing Li11Wen-Jing Li12Xiahenazi Aiyasiding13Xiahenazi Aiyasiding14Xiahenazi Aiyasiding15Zheng Lin16Zheng Lin17Zheng Lin18Wen Ding19Wen Ding20Wen Ding21Zi-Ying Zhou22Zi-Ying Zhou23Zi-Ying Zhou24Han Yan25Si Chen26Si Chen27Qi-Zhu Tang28Qi-Zhu Tang29Qi-Zhu Tang30Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, ChinaCardiovascular Research Institute of Wuhan University, Wuhan, ChinaHubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, ChinaCardiovascular Research Institute of Wuhan University, Wuhan, ChinaHubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, ChinaDepartment of Geriatrics, Renmin Hospital of Wuhan University, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, ChinaCardiovascular Research Institute of Wuhan University, Wuhan, ChinaHubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, ChinaCardiovascular Research Institute of Wuhan University, Wuhan, ChinaHubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, ChinaCardiovascular Research Institute of Wuhan University, Wuhan, ChinaHubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, ChinaCardiovascular Research Institute of Wuhan University, Wuhan, ChinaHubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, ChinaCardiovascular Research Institute of Wuhan University, Wuhan, ChinaHubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, ChinaCardiovascular Research Institute of Wuhan University, Wuhan, ChinaHubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, ChinaCardiovascular Research Institute of Wuhan University, Wuhan, ChinaCardiovascular Research Institute of Wuhan University, Wuhan, ChinaHubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, ChinaDepartment of Cardiology, Renmin Hospital of Wuhan University, Wuhan, ChinaCardiovascular Research Institute of Wuhan University, Wuhan, ChinaHubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, ChinaObjectives: 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.https://www.frontiersin.org/articles/10.3389/fphar.2021.716884/fullSestrin2cardiac hypertrophyfibrosisAMPKαoxidative stress |
| spellingShingle | 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 Frontiers in Pharmacology Sestrin2 cardiac hypertrophy fibrosis AMPKα oxidative stress |
| title | 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_short | 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 |
| topic | Sestrin2 cardiac hypertrophy fibrosis AMPKα oxidative stress |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2021.716884/full |
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