We tested the hypothesis that G protein–coupled receptor kinase 2 (GRK2) may be an important contributor to vascular endothelial dysfunction in diabetes. Human umbilical venous endothelial cells (HUVECs) were exposed to high glucose and high insulin (HG/HI) to mimic insulin-resistant diabetic conditions. GRK2 expression and membrane translocation were upregulated under HG/HI conditions. HG/HI did not modify activation of protein kinase B (Akt) and endothelial nitric-oxide synthase (eNOS), but GRK2 inhibition or small interfering RNA resulted in an increase in Akt and eNOS activation in HUVECs exposed to HG/HI. Our studies reveal that GRK2, which is upregulated by HG/HI, leads to a tonic inhibition of the insulin Akt/eNOS pathway in endothelial cells, providing new insight into the pathogenesis of diabetes-associated endothelial dysfunction.
See article at J Pharmacol Exp Ther 2014, 349:199–208.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics