GRK2 is a tonic inhibitor of Akt/eNOS signaling in human vascular endothelial cells under conditions of hyperglycemia with high insulin levels (851.12)

Abstract

The pathological role of GRK2 in vascular endothelial cell dysfunction was examined using human umbilical venous endothelial cells (HUVECs) exposed to high glucose and high insulin (HG/HI) in order to mimic insulin‐resistant diabetic conditions. GRK2 expression, membrane translocation, and activity were up‐regulated under HG/HI conditions. HG/HI did not activate Akt and eNOS, but GRK2 inhibitor or siRNA resulted in a significant increase in Akt and eNOS activation in HUVECs exposed to HG/HI. ERK1/2 activation was significantly increased after exposure to HG/HI, and the increase was prevented by GRK2 inhibitor or siRNA. In HEK293T cells which overexpressed GRK2, Akt activity was unchanged, while ERK1/2 activity was significantly raised. These data suggest that GRK2, which is up‐regulated under HG/HI conditions, leads to a tonic inhibition of the insulin downstream effectors, Akt and eNOS, with an increasing effect on ERK1/2 activity in endothelial cells.