Abstract 395: Regulation of G Protein-coupled Receptor Kinase 4 on AT1 Receptor Expression and Function in Artery
G protein-coupled receptor kinases (GRKs) constitute a family of seven mammalian serine/threonine protein kinases that phosphorylate/modify agonist-bound or activated G protein-coupled receptors (GPCRs) as their primary substrates. GRK4 is distinguished from other members of the GPCR family by its constitutive activity and limited tissue expression. Our previous study found that GRK4 variants (A142V, A486V and R65L) increases GRK4 activity; A142V transgenic mice develop hypertension with impaired sodium excretion by impairment of renal D1 dopamine receptor and augmented renal AT1 receptor expression and function. Whether there is GRK4 in the artery is not known. Our preliminary study found GRK4 expression in the artery, determined by immunoblotting and histochemistry. We hypothesize that GRK4 might also regulate AT1 receptor expression and function in vascular smooth muscle cells (VSMCs). A10 cells, an embryonic thoracic aortic smooth muscle cell lines, were transfected with A142V in this study. It resulted A142V increased AT1 receptor protein and mRNA expressions in A10 cells, meanwhile, decreased AT1 receptor phosphorylation. The regulation of A142V on AT1 receptor is physiological significance, because the angiotensin II-mediated VSMC proliferation was greater in the A142V transfected cells than in the control cells. Moreover, the vasoconstrictive effect of angiotensin II was greater in A142 transgenic mice than control mice. The above-mentioned phenomenon is confirmed by siRNA, GRK4 siRNA decreased AT1 receptor expression, increased AT1 receptor phosphorylation in primary cultured VSMCs from spontaneously hypertensive rats. Our further study found that there was co-localization between GRK4 and AT1 receptor in A10 cells, transfected with A142V increased the linkage of GRK4/AT1 receptor. It indicated that arterial GRK4 regulation of AT1 receptor expression and function, which might be engaged in the pathogenesis of hypertension.
- © 2012 by American Heart Association, Inc.