HuR (Human Antigen R) Regulates the Contraction of Vascular Smooth Muscle and Maintains Blood Pressure
HuR (Human Antigen R) Regulates the Contraction of Vascular Smooth Muscle and Maintains Blood Pressure
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DOI：
10.1161/atvbaha.119.313897
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发表时间：
2020-04-01
影响因子：
8.7
通讯作者：
Zhang, Wencheng
中科院分区：
文献类型：
--
作者：
Liu, Shanshan;Jiang, Xiuxin;Zhang, Wencheng
目的：人抗原R （human antigen R）是一种rna结合蛋白，通过结合富含腺苷酸-尿苷酸的元素参与调控mRNA的稳定性。本研究探讨HuR在平滑肌收缩和血压调节中的作用。方法与结果：将HuR（flox/flox）小鼠与α - sma （α -平滑肌肌动蛋白）-Cre小鼠杂交产生血管HuR(SMKO)（平滑肌特异性HuR敲除）小鼠。与CTR（对照）小鼠相比，HuR（SMKO）小鼠表现出高血压和心肌肥厚。高血压患者和自发性高血压大鼠主动脉中HuR水平降低，过表达HuR可降低自发性高血压大鼠的血压。从HuR（SMKO）小鼠分离的肠系膜动脉段对血管收缩剂的收缩反应增加。HuR（SMKO）小鼠的功能异常归因于RGS （g蛋白信号调节因子）蛋白RGS2、RGS4和RGS5 mRNA和蛋白水平的降低，导致细胞内钙含量增加。与此一致的是，RGS2、RGS4或RGS5的过表达降低了hur缺陷平滑肌细胞内钙离子的增加程度。最后，给药RGS2和RGS5逆转了HuR（SMKO）小鼠的血压升高。结论：HuR通过调节RGS的表达调节血管平滑肌收缩，维持血压。
Objective:HuR (human antigen R)-an RNA-binding protein-is involved in regulating mRNA stability by binding adenylate-uridylate-rich elements. This study explores the role of HuR in the regulation of smooth muscle contraction and blood pressure.Approach and Results:Vascular HuR(SMKO) (smooth muscle-specific HuR knockout) mice were generated by crossbreeding HuR(flox/flox) mice with alpha-SMA (alpha-smooth muscle actin)-Cre mice. As compared with CTR (control) mice, HuR(SMKO) mice showed hypertension and cardiac hypertrophy. HuR levels were decreased in aortas from hypertensive patients and SHRs (spontaneously hypertensive rats), and overexpression of HuR could lower the blood pressure of SHRs. Contractile response to vasoconstrictors was increased in mesenteric artery segments isolated from HuR(SMKO) mice. The functional abnormalities in HuR(SMKO) mice were attributed to decreased mRNA and protein levels of RGS (regulator of G-protein signaling) protein(s) RGS2, RGS4, and RGS5, which resulted in increased intracellular calcium increase. Consistently, the degree of intracellular calcium ion increase in HuR-deficient smooth muscle cells was reduced by overexpression of RGS2, RGS4, or RGS5. Finally, administration of RGS2 and RGS5 reversed the elevated blood pressure in HuR(SMKO) mice.Conclusions:Our findings indicate that HuR regulates vascular smooth muscle contraction and maintains blood pressure by modulating RGS expression.