Role of GRK4 in the regulation of arterial AT1 receptor in hypertension.
G-protein-coupled receptor kinase 4 (GRK4) gene variants, via impairment of renal dopamine receptor and enhancement of renin-angiotensin system functions, cause sodium retention and increase blood pressure. Whether GRK4 and the angiotensin type 1 receptor (AT(1)R) interact in the aorta is not known. We report that GRK4 is expressed in vascular smooth muscle cells of the aorta. Heterologous expression of the GRK4γ variant 142V in A10 cells increased AT(1)R protein expression and AT(1)R-mediated increase in intracellular calcium concentration. The increase in AT(1)R expression was related to an increase in AT(1)R mRNA expression via the NF-κB pathway. As compared with control, cells expressing GRK4γ 142V had greater NF-κB activity with more NF-κB bound to the AT(1)R promoter. The increased AT(1)R expression in cells expressing GRK4γ 142V was also associated with decreased AT(1)R degradation, which may be ascribed to lower AT(1)R phosphorylation. There was a direct interaction between GRK4γ and AT(1)R that was decreased by GRK4γ 142V. The regulation of AT(1)R expression by GRK4γ 142V in A10 cells was confirmed in GRK4γ 142V transgenic mice; AT(1)R expression was higher in the aorta of GRK4γ 142V transgenic mice than control GRK4γ wild-type mice. Angiotensin II-mediated vasoconstriction of the aorta was also higher in GRK4γ 142V than in wild-type transgenic mice. This study provides a mechanism by which GRK4, via regulation of arterial AT(1)R expression and function, participates in the pathogenesis of conduit vessel abnormalities in hypertension.
Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing 400042, PR China. chunyuzeng01@163.com.
Ken
K
Chen
Chunjiang
C
Fu
Caiyu
C
Chen
Li
L
Liu
Hongmei
H
Ren
Yu
Y
Han
Jian
J
Yang
Duofen
D
He
Lin
L
Zhou
Zhiwei
Z
Yang
Lianfeng
L
Zhang
Pedro A
PA
Jose
Chunyu
C
Zeng
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology; D002478:Cells, Cultured; D054771:G-Protein-Coupled Receptor Kinase 4 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006977:Hypertension, Renal / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology; D014161:Transduction, Genetic
D034741:RNA, Small Interfering; D044140:Receptor, Angiotensin, Type 1; D054771:G-Protein-Coupled Receptor Kinase 4; C517855:GRK4 protein, human
G-protein–coupled receptor kinase 4; arteries; hypertension; receptor, angiotensin, type 1