Essential Role Of High Glucose-Induced Overexpression Of PKCß And PKCδ In GLP-1 Resistance In Rodent Cardiomyocytes.
Diabetes Metab Syndr Obes
; 12: 2289-2302, 2019.
Article
en En
| MEDLINE
| ID: mdl-31807042
ABSTRACT
PURPOSE:
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 PKCß 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 PKCß 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 PKCß 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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Idioma:
En
Revista:
Diabetes Metab Syndr Obes
Año:
2019
Tipo del documento:
Article