Abstract
G protein-coupled receptor kinase 4 (GRK4) gene variants or increased GRK4 expression, via impairment of renal dopamine receptor and enhancement of renin angiotensin system function, impairs renal sodium excretion, resulting in sodium retention and an increase in blood pressure. Increased aortic stiffness, a risk factor in cardiovascular disease, may be related to increased activity of the renin-angiotensin system Whether or not GRK4 and the angiotensin type 1 receptor (AT 1 R) interact in the aorta is not known. We now report that GRK4 is expressed in vascular smooth muscle cells (VSMCs) of the aorta. Exogenous expression of the GRK4 variant 142V in aortic A10 cells increased AT 1 R protein expression and AT 1 R-mediated increase in intracellular calcium concentration. The increased AT 1 R expression was caused by an increase in AT 1 R mRNA expression via NF-κB, because blockade of NF-κB abolished those effects of GRK4 A142V. As compared with control (vector-transfected) cells, cells expressing 142V had higher NF-kB activity and more NF-kB bound to AT 1 R promoter. The increased AT 1 R expression in cells expressing GRK4 142V was associated with decreased AT 1 R degradation, which was ascribed to the lower AT 1 R phosphorylation. There was direct interaction between GRK4 and AT 1 R in A10 cells which was decreased by GRK4 that could have caused the lower AT 1 R phosphorylation and degradation. The regulation of GRK4 of AT 1 R expression was confirmed in GRK4142V transgenic mice, the AT 1 R expression was higher, while AT 1 R phosphorylation was lower in aorta in GRK4 142V than control mice. Angiotensin II- mediated vasoconstriction was higher in A142V mice. This study provides a mechanism that GRK4, via regulation of arterial AT 1 R expression and function, engaged into the pathogenesis of hypertension.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call