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MST1 coordinately regulates autophagy and apoptosis in diabetic cardiomyopathy in mice

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... Full description

Journal Title: Diabetologia 2016-08-10, Vol.59 (11), p.2435-2447
Main Author: Zhang, Mingming
Other Authors: Zhang, Lei , Hu, Jianqiang , Lin, Jie , Wang, Tingting , Duan, Yu , Man, Wanrong , Feng, Jiaxu , Sun, Lei , Jia, Hongbing , Li, Congye , Zhang, Rongqing , Wang, Haichang , Sun, Dongdong
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: Berlin/Heidelberg: Springer Berlin Heidelberg
ID: ISSN: 0012-186X
Link: https://www.ncbi.nlm.nih.gov/pubmed/27510910
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recordid: cdi_crossref_primary_10_1007_s00125_016_4070_9
title: MST1 coordinately regulates autophagy and apoptosis in diabetic cardiomyopathy in mice
format: Article
creator:
  • Zhang, Mingming
  • Zhang, Lei
  • Hu, Jianqiang
  • Lin, Jie
  • Wang, Tingting
  • Duan, Yu
  • Man, Wanrong
  • Feng, Jiaxu
  • Sun, Lei
  • Jia, Hongbing
  • Li, Congye
  • Zhang, Rongqing
  • Wang, Haichang
  • Sun, Dongdong
subjects:
  • Adenosine Triphosphate - metabolism
  • Animals
  • Apoptosis
  • Apoptosis - genetics
  • Apoptosis - physiology
  • Article
  • Autophagy - genetics
  • Autophagy - physiology
  • Cardiomyopathy
  • Cells, Cultured
  • Citrate (si)-Synthase - metabolism
  • Diabetes Mellitus, Experimental - genetics
  • Diabetes Mellitus, Experimental - metabolism
  • Diabetic Cardiomyopathies - genetics
  • Diabetic Cardiomyopathies - metabolism
  • Echocardiography
  • Genetic engineering
  • Heart diseases
  • Hepatocyte Growth Factor - genetics
  • Hepatocyte Growth Factor - metabolism
  • Human Physiology
  • Immunoblotting
  • Internal Medicine
  • Male
  • Medicine
  • Medicine & Public Health
  • Membrane Potential, Mitochondrial - genetics
  • Membrane Potential, Mitochondrial - physiology
  • Metabolic Diseases
  • Mice
  • Mice, Knockout
  • Microscopy, Electron
  • Positron-Emission Tomography
  • Proto-Oncogene Proteins - genetics
  • Proto-Oncogene Proteins - metabolism
ispartof: Diabetologia, 2016-08-10, Vol.59 (11), p.2435-2447
description: 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.
language: eng
source:
identifier: ISSN: 0012-186X
fulltext: no_fulltext
issn:
  • 0012-186X
  • 1432-0428
url: Link


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titleMST1 coordinately regulates autophagy and apoptosis in diabetic cardiomyopathy in mice
creatorZhang, Mingming ; Zhang, Lei ; Hu, Jianqiang ; Lin, Jie ; Wang, Tingting ; Duan, Yu ; Man, Wanrong ; Feng, Jiaxu ; Sun, Lei ; Jia, Hongbing ; Li, Congye ; Zhang, Rongqing ; Wang, Haichang ; Sun, Dongdong
creatorcontribZhang, Mingming ; Zhang, Lei ; Hu, Jianqiang ; Lin, Jie ; Wang, Tingting ; Duan, Yu ; Man, Wanrong ; Feng, Jiaxu ; Sun, Lei ; Jia, Hongbing ; Li, Congye ; Zhang, Rongqing ; Wang, Haichang ; Sun, Dongdong
descriptionAims/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.
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subjectAdenosine Triphosphate - metabolism ; Animals ; Apoptosis ; Apoptosis - genetics ; Apoptosis - physiology ; Article ; Autophagy - genetics ; Autophagy - physiology ; Cardiomyopathy ; Cells, Cultured ; Citrate (si)-Synthase - metabolism ; Diabetes Mellitus, Experimental - genetics ; Diabetes Mellitus, Experimental - metabolism ; Diabetic Cardiomyopathies - genetics ; Diabetic Cardiomyopathies - metabolism ; Echocardiography ; Genetic engineering ; Heart diseases ; Hepatocyte Growth Factor - genetics ; Hepatocyte Growth Factor - metabolism ; Human Physiology ; Immunoblotting ; Internal Medicine ; Male ; Medicine ; Medicine & Public Health ; Membrane Potential, Mitochondrial - genetics ; Membrane Potential, Mitochondrial - physiology ; Metabolic Diseases ; Mice ; Mice, Knockout ; Microscopy, Electron ; Positron-Emission Tomography ; Proto-Oncogene Proteins - genetics ; Proto-Oncogene Proteins - metabolism
ispartofDiabetologia, 2016-08-10, Vol.59 (11), p.2435-2447
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9Jia, Hongbing
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descriptionAims/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.
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1Animals
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4Apoptosis - physiology
5Article
6Autophagy - genetics
7Autophagy - physiology
8Cardiomyopathy
9Cells, Cultured
10Citrate (si)-Synthase - metabolism
11Diabetes Mellitus, Experimental - genetics
12Diabetes Mellitus, Experimental - metabolism
13Diabetic Cardiomyopathies - genetics
14Diabetic Cardiomyopathies - metabolism
15Echocardiography
16Genetic engineering
17Heart diseases
18Hepatocyte Growth Factor - genetics
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20Human Physiology
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23Male
24Medicine
25Medicine & Public Health
26Membrane Potential, Mitochondrial - genetics
27Membrane Potential, Mitochondrial - physiology
28Metabolic Diseases
29Mice
30Mice, Knockout
31Microscopy, Electron
32Positron-Emission Tomography
33Proto-Oncogene Proteins - genetics
34Proto-Oncogene Proteins - metabolism
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titleMST1 coordinately regulates autophagy and apoptosis in diabetic cardiomyopathy in mice
authorZhang, Mingming ; Zhang, Lei ; Hu, Jianqiang ; Lin, Jie ; Wang, Tingting ; Duan, Yu ; Man, Wanrong ; Feng, Jiaxu ; Sun, Lei ; Jia, Hongbing ; Li, Congye ; Zhang, Rongqing ; Wang, Haichang ; Sun, Dongdong
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abstractAims/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.
copBerlin/Heidelberg
pubSpringer Berlin Heidelberg
pmid27510910
doi10.1007/s00125-016-4070-9
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