Diabetes, Metabolic Syndrome and Obesity (Nov 2019)
Essential Role Of High Glucose-Induced Overexpression Of PKCβ And PKCδ In GLP-1 Resistance In Rodent Cardiomyocytes
Abstract
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 [email protected]; [email protected]: 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
