Role of GRK4 in the Regulation of Arterial AT1 Receptor in Hypertension
Role of GRK4 in the Regulation of Arterial AT1 Receptor in Hypertension
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GRK4 在高血压动脉 AT1 受体调节中的作用
DOI：
10.1161/hypertensionaha.113.01766
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发表时间：
2014-02-01
期刊：
影响因子：
8.3
通讯作者：
Zeng, Chunyu
中科院分区：
文献类型：
--
作者：
Chen, Ken;Fu, Chunjiang;Zeng, Chunyu
G蛋白偶联受体激酶4（GRK 4）基因变异通过损害肾脏多巴胺受体和增强肾素-血管紧张素系统功能，引起钠潴留和血压升高。GRK 4和血管紧张素1型受体（AT 1 R）是否在主动脉中相互作用尚不清楚.我们报告GRK 4在主动脉的血管平滑肌细胞中表达。GRK 4 γ变体142 V在A10细胞中的异源表达增加了AT（1）R蛋白表达和AT（1）R介导的细胞内钙浓度增加。AT（1）R表达的增加与通过NF-κ B途径增加AT（1）R mRNA表达有关。与对照组相比，表达GRK 4 γ 142 V的细胞具有更高的NF-κ B活性，更多的NF-κ B与AT（1）R启动子结合。在表达GRK 4 γ 142 V的细胞中，AT（1）R表达的增加也与AT（1）R降解的减少有关，这可能归因于AT（1）R磷酸化的降低。GRK 4 γ和AT（1）R之间存在直接相互作用，GRK 4 γ 142 V可降低这种相互作用。在GRK 4 γ 142 V转基因小鼠中证实了GRK 4 γ 142 V对A10细胞中AT（1）R表达的调节; GRK 4 γ 142 V转基因小鼠的主动脉中AT（1）R表达高于对照GRK 4 γ野生型小鼠。GRK 4 γ 142 V中血管紧张素II介导的主动脉血管收缩也高于野生型转基因小鼠。本研究提供了GRK 4通过调节动脉AT（1）R表达和功能参与高血压导管血管异常发病机制的机制。
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 GRK4 gamma 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-kappa B pathway. As compared with control, cells expressing GRK4 gamma 142V had greater NF-kappa B activity with more NF-kappa B bound to the AT(1)R promoter. The increased AT(1)R expression in cells expressing GRK4 gamma 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 GRK4 gamma and AT(1)R that was decreased by GRK4 gamma 142V. The regulation of AT(1)R expression by GRK4 gamma 142V in A10 cells was confirmed in GRK4 gamma 142V transgenic mice; AT(1)R expression was higher in the aorta of GRK4 gamma 142V transgenic mice than control GRK4 gamma wild-type mice. Angiotensin II-mediated vasoconstriction of the aorta was also higher in GRK4 gamma 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.