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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| Formato: | article |
| Lenguaje: | EN |
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Dove Medical Press
2019
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| Acceso en línea: | https://doaj.org/article/df96b09f004947aab5dce40f45978387 |
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| Sumario: | 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 |
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