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MST1 coordinately regulates autophagy and apoptosis in diabetic cardiomyopathy in mice.
Diabetologia. 2016 11; 59(11):2435-2447.D

Abstract

AIMS/HYPOTHESIS

Diabetic cardiomyopathy (DCM) is associated with suppressed autophagy and augmented apoptosis in the heart although the interplay between the two remains elusive. The ability of mammalian sterile 20-like kinase 1 to regulate both autophagy and apoptosis prompted us to investigate it as a possible candidate in the progression of DCM.

METHODS

Wild-type, Mst1 (also known as Stk4) transgenic and Mst1-knockout mice were challenged with streptozotocin to induce experimental diabetes. In addition, cultured neonatal mouse cardiomyocytes were subjected to simulated diabetes to probe mechanisms.

RESULTS

Mst1 knockout alleviated while Mst1 overexpression aggravated cardiac dysfunction in diabetes. Diabetic Mst1 transgenic mice exhibited decreased LC3 expression and enhanced protein aggregation. In contrast, typical autophagosomes were observed in diabetic Mst1-knockout mice with increased LC3 expression and reduced protein aggregation. Mst1 downregulation promoted autophagic flux as demonstrated by increased LC3-II and decreased p62 expression in the presence of bafilomycin A1. Furthermore, Mst1 overexpression increased, while Mst1 knockout decreased, cardiomyocyte apoptosis both in vivo and in vitro. Co-immunoprecipitation assays showed that Mst1 overexpression promoted Beclin1 binding to B cell lymphoma 2 (Bcl-2) and induced dissociation of Bcl-2 from Bax in diabetic mice. Conversely, Mst1 knockout disrupted the Beclin1-Bcl-2 complex and enhanced the interaction between Bcl-2 and Bax.

CONCLUSIONS/INTERPRETATION

Mst1 knockout restores autophagy and protects against apoptosis in cardiomyocytes, en route to the rescue against DCM.

Authors+Show Affiliations

Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Xi'an, Shaanxi, 710038, People's Republic of China. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Xi'an, Shaanxi, 710038, People's Republic of China. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Xi'an, Shaanxi, 710038, People's Republic of China. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Xi'an, Shaanxi, 710038, People's Republic of China. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Xi'an, Shaanxi, 710038, People's Republic of China. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Xi'an, Shaanxi, 710038, People's Republic of China. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Xi'an, Shaanxi, 710038, People's Republic of China. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Xi'an, Shaanxi, 710038, People's Republic of China. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.Department of Cadre's Ward, PLA 323 Hospital, Xi'an, People's Republic of China.Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Xi'an, Shaanxi, 710038, People's Republic of China. wanghc@fmmu.edu.cn. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China. wanghc@fmmu.edu.cn.Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Xi'an, Shaanxi, 710038, People's Republic of China. wintersun3@gmail.com. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China. wintersun3@gmail.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27510910

Citation

Zhang, Mingming, et al. "MST1 Coordinately Regulates Autophagy and Apoptosis in Diabetic Cardiomyopathy in Mice." Diabetologia, vol. 59, no. 11, 2016, pp. 2435-2447.
Zhang M, Zhang L, Hu J, et al. MST1 coordinately regulates autophagy and apoptosis in diabetic cardiomyopathy in mice. Diabetologia. 2016;59(11):2435-2447.
Zhang, M., Zhang, L., Hu, J., Lin, J., Wang, T., Duan, Y., Man, W., Feng, J., Sun, L., Jia, H., Li, C., Zhang, R., Wang, H., & Sun, D. (2016). MST1 coordinately regulates autophagy and apoptosis in diabetic cardiomyopathy in mice. Diabetologia, 59(11), 2435-2447. https://doi.org/10.1007/s00125-016-4070-9
Zhang M, et al. MST1 Coordinately Regulates Autophagy and Apoptosis in Diabetic Cardiomyopathy in Mice. Diabetologia. 2016;59(11):2435-2447. PubMed PMID: 27510910.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MST1 coordinately regulates autophagy and apoptosis in diabetic cardiomyopathy in mice. AU - Zhang,Mingming, AU - Zhang,Lei, AU - Hu,Jianqiang, AU - Lin,Jie, AU - Wang,Tingting, AU - Duan,Yu, AU - Man,Wanrong, AU - Feng,Jiaxu, AU - Sun,Lei, AU - Jia,Hongbing, AU - Li,Congye, AU - Zhang,Rongqing, AU - Wang,Haichang, AU - Sun,Dongdong, Y1 - 2016/08/10/ PY - 2016/04/03/received PY - 2016/07/14/accepted PY - 2016/8/12/entrez PY - 2016/8/12/pubmed PY - 2017/8/29/medline KW - Autophagy KW - Beclin1 KW - Diabetes KW - MST1 SP - 2435 EP - 2447 JF - Diabetologia JO - Diabetologia VL - 59 IS - 11 N2 - AIMS/HYPOTHESIS: Diabetic cardiomyopathy (DCM) is associated with suppressed autophagy and augmented apoptosis in the heart although the interplay between the two remains elusive. The ability of mammalian sterile 20-like kinase 1 to regulate both autophagy and apoptosis prompted us to investigate it as a possible candidate in the progression of DCM. METHODS: Wild-type, Mst1 (also known as Stk4) transgenic and Mst1-knockout mice were challenged with streptozotocin to induce experimental diabetes. In addition, cultured neonatal mouse cardiomyocytes were subjected to simulated diabetes to probe mechanisms. RESULTS: Mst1 knockout alleviated while Mst1 overexpression aggravated cardiac dysfunction in diabetes. Diabetic Mst1 transgenic mice exhibited decreased LC3 expression and enhanced protein aggregation. In contrast, typical autophagosomes were observed in diabetic Mst1-knockout mice with increased LC3 expression and reduced protein aggregation. Mst1 downregulation promoted autophagic flux as demonstrated by increased LC3-II and decreased p62 expression in the presence of bafilomycin A1. Furthermore, Mst1 overexpression increased, while Mst1 knockout decreased, cardiomyocyte apoptosis both in vivo and in vitro. Co-immunoprecipitation assays showed that Mst1 overexpression promoted Beclin1 binding to B cell lymphoma 2 (Bcl-2) and induced dissociation of Bcl-2 from Bax in diabetic mice. Conversely, Mst1 knockout disrupted the Beclin1-Bcl-2 complex and enhanced the interaction between Bcl-2 and Bax. CONCLUSIONS/INTERPRETATION: Mst1 knockout restores autophagy and protects against apoptosis in cardiomyocytes, en route to the rescue against DCM. SN - 1432-0428 UR - https://www.unboundmedicine.com/medline/citation/27510910/MST1_coordinately_regulates_autophagy_and_apoptosis_in_diabetic_cardiomyopathy_in_mice_ L2 - https://doi.org/10.1007/s00125-016-4070-9 DB - PRIME DP - Unbound Medicine ER -