Essential Role Of High Glucose-Induced Overexpression Of PKCβ And PKCδ In GLP-1 Resistance In Rodent Cardiomyocytes

Xietian Pan,1 Jiangwei Chen,2 Tingting Wang,1 Mingming Zhang,1 Haichang Wang,1 Haokao Gao2 1Department of Cardiology, Tangdu Hospital, Air Force Medical University, Xi’an, People’s Republic of China; 2Department of Cardiology, Xijing Hospital, Air Force Medical University, Xi&...

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Autores principales:	Pan X, Chen J, Wang T, Zhang M, Wang H, Gao H
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	ischemia/reperfusion injury protein kinase c glp-1 resistance diabetic cardiomyocytes Specialties of internal medicine RC581-951
Acceso en línea:	https://doaj.org/article/df96b09f004947aab5dce40f45978387
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spelling	oai:doaj.org-article:df96b09f004947aab5dce40f459783872021-12-02T06:42:29ZEssential Role Of High Glucose-Induced Overexpression Of PKCβ And PKCδ In GLP-1 Resistance In Rodent Cardiomyocytes1178-7007https://doaj.org/article/df96b09f004947aab5dce40f459783872019-11-01T00:00:00Zhttps://www.dovepress.com/essential-role-of-high-glucose-induced-overexpression-of-pkcbeta-and-p-peer-reviewed-article-DMSOhttps://doaj.org/toc/1178-7007Xietian Pan,1 Jiangwei Chen,2 Tingting Wang,1 Mingming Zhang,1 Haichang Wang,1 Haokao Gao2 1Department of Cardiology, Tangdu Hospital, Air Force Medical University, Xi’an, People’s Republic of China; 2Department of Cardiology, Xijing Hospital, Air Force Medical University, Xi’an, People’s Republic of ChinaCorrespondence: Haokao Gao; Haichang WangDepartment of Cardiology, Xijing Hospital, Air Force Medical University, Xi’an, People’s Republic of ChinaTel +86 029 84774114Email hk_gao@163.com; wanghc@fmmu.edu.cnPurpose: Myocardia in diabetic patients exhibit increased vulnerability after ischemia/reperfusion injury (IRI). It has been demonstrated that glucagon-like peptide-1 (GLP-1) has a protective effect on cardiomyocytes. Protein kinase C (PKC) acts as a key regulator of many signaling pathways including oxidative stress and apoptosis. Our hypothesis is that increased vulnerability of myocardia in diabetic patients is partly due to GLP-1 resistance. The aim of this study was to explore the role of PKC in GLP-1 resistance in diabetic cardiomyocytes.Methods: Cardiac function of diabetic or non-diabetic mice after myocardial IRI was detected with or without administration of GLP-1 analog exendin-4. Impacts of diabetes mellitus on GLP-1R expression in myocardia after IRI were accessed by Western blot. By transfecting PKC isoforms siRNA, in vitro study helped to identify the exact PKC isoforms which contributed to the downregulatio n of GLP-1R or impaired post-receptor signaling pathways in rodent cardiomyocytes (H9C2 cells) cultured by high glucose.Results: The cardioprotective effects of endogenous GLP-1 were impaired in diabetic mice after myocardial IRI and administration of exendin-4 had no significant effects in restoring cardiac function. GLP-1 receptor (GLP-1R) expression decreased in H9C2 cells cultured by high glucose and knockdown of PKCβ partly restored GLP-1R expression. Overexpression of PKCδ induced by high glucose in H9C2 cells impaired GLP-1 post-receptor anti-apoptotic signaling pathways by inhibition of Akt phosphorylation. Knockdown of both PKCβ and PKCδ significantly restored cardioprotective effects of GLP-1 in H9C2 cells cultured by high glucose.Conclusion: Our study found out a new mechanism of GLP-1 resistance that high glucose-induced overexpression of PKCβ and PKCδ impaired cardioprotective effects of GLP-1 by downregulation of GLP-1R and inhibition of GLP-1 post-receptor anti-apoptotic signaling pathways, thus provided a new perspective in treating myocardial IRI in diabetic patients.Keywords: ischemia/reperfusion injury, protein kinase C, GLP-1 resistance, diabetic cardiomyocytesPan XChen JWang TZhang MWang HGao HDove Medical Pressarticleischemia/reperfusion injuryprotein kinase cglp-1 resistancediabetic cardiomyocytesSpecialties of internal medicineRC581-951ENDiabetes, Metabolic Syndrome and Obesity: Targets and Therapy, Vol Volume 12, Pp 2289-2302 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	ischemia/reperfusion injury protein kinase c glp-1 resistance diabetic cardiomyocytes Specialties of internal medicine RC581-951
spellingShingle	ischemia/reperfusion injury protein kinase c glp-1 resistance diabetic cardiomyocytes Specialties of internal medicine RC581-951 Pan X Chen J Wang T Zhang M Wang H Gao H Essential Role Of High Glucose-Induced Overexpression Of PKCβ And PKCδ In GLP-1 Resistance In Rodent Cardiomyocytes
description	Xietian Pan,1 Jiangwei Chen,2 Tingting Wang,1 Mingming Zhang,1 Haichang Wang,1 Haokao Gao2 1Department of Cardiology, Tangdu Hospital, Air Force Medical University, Xi’an, People’s Republic of China; 2Department of Cardiology, Xijing Hospital, Air Force Medical University, Xi’an, People’s Republic of ChinaCorrespondence: Haokao Gao; Haichang WangDepartment of Cardiology, Xijing Hospital, Air Force Medical University, Xi’an, People’s Republic of ChinaTel +86 029 84774114Email hk_gao@163.com; wanghc@fmmu.edu.cnPurpose: Myocardia in diabetic patients exhibit increased vulnerability after ischemia/reperfusion injury (IRI). It has been demonstrated that glucagon-like peptide-1 (GLP-1) has a protective effect on cardiomyocytes. Protein kinase C (PKC) acts as a key regulator of many signaling pathways including oxidative stress and apoptosis. Our hypothesis is that increased vulnerability of myocardia in diabetic patients is partly due to GLP-1 resistance. The aim of this study was to explore the role of PKC in GLP-1 resistance in diabetic cardiomyocytes.Methods: Cardiac function of diabetic or non-diabetic mice after myocardial IRI was detected with or without administration of GLP-1 analog exendin-4. Impacts of diabetes mellitus on GLP-1R expression in myocardia after IRI were accessed by Western blot. By transfecting PKC isoforms siRNA, in vitro study helped to identify the exact PKC isoforms which contributed to the downregulatio n of GLP-1R or impaired post-receptor signaling pathways in rodent cardiomyocytes (H9C2 cells) cultured by high glucose.Results: The cardioprotective effects of endogenous GLP-1 were impaired in diabetic mice after myocardial IRI and administration of exendin-4 had no significant effects in restoring cardiac function. GLP-1 receptor (GLP-1R) expression decreased in H9C2 cells cultured by high glucose and knockdown of PKCβ partly restored GLP-1R expression. Overexpression of PKCδ induced by high glucose in H9C2 cells impaired GLP-1 post-receptor anti-apoptotic signaling pathways by inhibition of Akt phosphorylation. Knockdown of both PKCβ and PKCδ significantly restored cardioprotective effects of GLP-1 in H9C2 cells cultured by high glucose.Conclusion: Our study found out a new mechanism of GLP-1 resistance that high glucose-induced overexpression of PKCβ and PKCδ impaired cardioprotective effects of GLP-1 by downregulation of GLP-1R and inhibition of GLP-1 post-receptor anti-apoptotic signaling pathways, thus provided a new perspective in treating myocardial IRI in diabetic patients.Keywords: ischemia/reperfusion injury, protein kinase C, GLP-1 resistance, diabetic cardiomyocytes
format	article
author	Pan X Chen J Wang T Zhang M Wang H Gao H
author_facet	Pan X Chen J Wang T Zhang M Wang H Gao H
author_sort	Pan X
title	Essential Role Of High Glucose-Induced Overexpression Of PKCβ And PKCδ In GLP-1 Resistance In Rodent Cardiomyocytes
title_short	Essential Role Of High Glucose-Induced Overexpression Of PKCβ And PKCδ In GLP-1 Resistance In Rodent Cardiomyocytes
title_full	Essential Role Of High Glucose-Induced Overexpression Of PKCβ And PKCδ In GLP-1 Resistance In Rodent Cardiomyocytes
title_fullStr	Essential Role Of High Glucose-Induced Overexpression Of PKCβ And PKCδ In GLP-1 Resistance In Rodent Cardiomyocytes
title_full_unstemmed	Essential Role Of High Glucose-Induced Overexpression Of PKCβ And PKCδ In GLP-1 Resistance In Rodent Cardiomyocytes
title_sort	essential role of high glucose-induced overexpression of pkcβ and pkcδ in glp-1 resistance in rodent cardiomyocytes
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/df96b09f004947aab5dce40f45978387
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Essential Role Of High Glucose-Induced Overexpression Of PKCβ And PKCδ In GLP-1 Resistance In Rodent Cardiomyocytes

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