Exendin-4 Protects against Hyperglycemia-Induced Cardiomyocyte Pyroptosis via the AMPK-TXNIP Pathway

Diabetic cardiomyopathy is a common cardiac condition in patients with diabetes mellitus, which results in cardiac hypertrophy and subsequent heart failure. Chronic inflammation in the diabetic heart results in loss of cardiomyocytes and subsequentially cardiac dysfunction. Accumulated evidence impl...

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Main Authors: Hong Wei, Rui Bu, Qinghui Yang, Jing Jia, Tao Li, Qiuping Wang, Yanjun Chen
Format: Article
Language:English
Published: Hindawi Limited 2019-01-01
Series:Journal of Diabetes Research
Online Access:http://dx.doi.org/10.1155/2019/8905917
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spelling doaj-5e9f5f18365149eeb4cb4c96b9b6507b2020-11-24T23:51:06ZengHindawi LimitedJournal of Diabetes Research2314-67452314-67532019-01-01201910.1155/2019/89059178905917Exendin-4 Protects against Hyperglycemia-Induced Cardiomyocyte Pyroptosis via the AMPK-TXNIP PathwayHong Wei0Rui Bu1Qinghui Yang2Jing Jia3Tao Li4Qiuping Wang5Yanjun Chen6Department of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, ChinaDepartment of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, ChinaDepartment of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, ChinaDepartment of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, ChinaDepartment of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, ChinaDepartment of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, ChinaDepartment of Cardiology, Peking University Shenzhen Hospital, Shenzhen, ChinaDiabetic cardiomyopathy is a common cardiac condition in patients with diabetes mellitus, which results in cardiac hypertrophy and subsequent heart failure. Chronic inflammation in the diabetic heart results in loss of cardiomyocytes and subsequentially cardiac dysfunction. Accumulated evidence implicated pyroptosis as a vital contributor to the hyperglycemia-induced cardiac inflammatory response. Exendin-4, a GLP analog, promotes survival of cardiomyocytes in cardiovascular diseases, including diabetic cardiomyopathy. However, the role of Exendin-4 in cardiac pyroptosis remains to be elucidated. Our study revealed that Exendin-4 treatment protected against heart remolding and dysfunction and attenuated cardiac inflammation in high-fat diet-fed rats. The activity of caspase-1 and production of pyroptotic cytokines were significantly inhibited by Exendin-4 treatment in the diabetic heart and in high glucose-treated cardiomyocytes as well. In an effort to understand the signaling mechanisms underlying the antipyroptotic property of Exendin-4, we found that blockade of AMPK, an oxidative stress sensor, activity diminished the antipyroptotic property of Exendin-4. Phosphorylation of AMPK resulted in degeneration of TXNIP that promoted the activation of the NLRP3 inflammasome. Exendin-4 treatment decreased the protein level of TXNIP. Moreover, RNA silencing of TXNIP mimicked the antipyroptotic actions of Exendin-4. These findings promoted us to propose a new signaling pathway mediating cardioprotective effect of Exendin-4 under hyperglycemic conditions: Exendin-4 → ROS↓ → pAMPK↑ → TXNIP↓ → caspase-1↓ → IL-1β and IL-18↓ → pyroptosis↓. In general, our study identified Exendin-4 as a pyroptotic inhibitor protecting against hyperglycemia-induced cardiomyocyte pyroptosis via the AMPK-TXNIP pathway.http://dx.doi.org/10.1155/2019/8905917
collection DOAJ
language English
format Article
sources DOAJ
author Hong Wei
Rui Bu
Qinghui Yang
Jing Jia
Tao Li
Qiuping Wang
Yanjun Chen
spellingShingle Hong Wei
Rui Bu
Qinghui Yang
Jing Jia
Tao Li
Qiuping Wang
Yanjun Chen
Exendin-4 Protects against Hyperglycemia-Induced Cardiomyocyte Pyroptosis via the AMPK-TXNIP Pathway
Journal of Diabetes Research
author_facet Hong Wei
Rui Bu
Qinghui Yang
Jing Jia
Tao Li
Qiuping Wang
Yanjun Chen
author_sort Hong Wei
title Exendin-4 Protects against Hyperglycemia-Induced Cardiomyocyte Pyroptosis via the AMPK-TXNIP Pathway
title_short Exendin-4 Protects against Hyperglycemia-Induced Cardiomyocyte Pyroptosis via the AMPK-TXNIP Pathway
title_full Exendin-4 Protects against Hyperglycemia-Induced Cardiomyocyte Pyroptosis via the AMPK-TXNIP Pathway
title_fullStr Exendin-4 Protects against Hyperglycemia-Induced Cardiomyocyte Pyroptosis via the AMPK-TXNIP Pathway
title_full_unstemmed Exendin-4 Protects against Hyperglycemia-Induced Cardiomyocyte Pyroptosis via the AMPK-TXNIP Pathway
title_sort exendin-4 protects against hyperglycemia-induced cardiomyocyte pyroptosis via the ampk-txnip pathway
publisher Hindawi Limited
series Journal of Diabetes Research
issn 2314-6745
2314-6753
publishDate 2019-01-01
description Diabetic cardiomyopathy is a common cardiac condition in patients with diabetes mellitus, which results in cardiac hypertrophy and subsequent heart failure. Chronic inflammation in the diabetic heart results in loss of cardiomyocytes and subsequentially cardiac dysfunction. Accumulated evidence implicated pyroptosis as a vital contributor to the hyperglycemia-induced cardiac inflammatory response. Exendin-4, a GLP analog, promotes survival of cardiomyocytes in cardiovascular diseases, including diabetic cardiomyopathy. However, the role of Exendin-4 in cardiac pyroptosis remains to be elucidated. Our study revealed that Exendin-4 treatment protected against heart remolding and dysfunction and attenuated cardiac inflammation in high-fat diet-fed rats. The activity of caspase-1 and production of pyroptotic cytokines were significantly inhibited by Exendin-4 treatment in the diabetic heart and in high glucose-treated cardiomyocytes as well. In an effort to understand the signaling mechanisms underlying the antipyroptotic property of Exendin-4, we found that blockade of AMPK, an oxidative stress sensor, activity diminished the antipyroptotic property of Exendin-4. Phosphorylation of AMPK resulted in degeneration of TXNIP that promoted the activation of the NLRP3 inflammasome. Exendin-4 treatment decreased the protein level of TXNIP. Moreover, RNA silencing of TXNIP mimicked the antipyroptotic actions of Exendin-4. These findings promoted us to propose a new signaling pathway mediating cardioprotective effect of Exendin-4 under hyperglycemic conditions: Exendin-4 → ROS↓ → pAMPK↑ → TXNIP↓ → caspase-1↓ → IL-1β and IL-18↓ → pyroptosis↓. In general, our study identified Exendin-4 as a pyroptotic inhibitor protecting against hyperglycemia-induced cardiomyocyte pyroptosis via the AMPK-TXNIP pathway.
url http://dx.doi.org/10.1155/2019/8905917
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