G PROTEIN-COUPLED RECEPTOR KINASE-5 IN CULTURED VASCULAR SMOOTH-MUSCLE CELLS AND RAT AORTA - REGULATION BY ANGIOTENSIN-II AND HYPERTENSION

GRK5, a recently cloned member of the G protein-coupled receptor kinas e family, has been shown to phosphorylate and participate in the desen sitization of angiotensin II (Ang II) type 1A (AT(1A)) receptors. In t his study, the effect of angiotensin II on GRK5 expression was examine d in cultured vascular smooth muscle cells and aortas of Ang II-infuse d hypertensive rats. In vascular smooth muscle cells, Ang II (100 nM) up-regulated GRK5 mRNA as early as 1 h, with a peak at 16 h. This up-r egulation was dose- and calcium-dependent. The increase in GRK5 mRNA w as reflected in a smaller increase in protein expression, which noneth eless had functional significance since AT(1) receptor phosphorylation was increased and phospholipase C activation was decreased following prolonged incubation with Ang II. In aortas of Ang II-infused hyperten sive rats, both GRK5 mRNA and protein levels increased similar to 3-fo ld compared with sham-operated rats at 5 and 7 days, respectively. Thi s up-regulation was blocked either by losartan or by the nonspecific v asodilator hydralazine. Since a subpressor dose of Ang II did not incr ease GRK5 mRNA levels and norepinephrine infusion also increased GRK5 mRNA expression, we conclude that Ang II-induced GRK5 up-regulation in rat aortas may be due to hypertension per se. Hormone-and hemodynamic stress-induced GRK5 regulation may provide a novel molecular basis fo r long-term regulation of agonist sensitivity of vascular cells.