Eukaryotic elongation factor 2 kinase regulates the development of hypertension through oxidative stress-dependent vascular inflammation
Eukaryotic elongation factor 2 kinase regulates the development of hypertension through oxidative stress-dependent vascular inflammation
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DOI：
10.1152/ajpheart.00373.2013
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发表时间：
2013-09-01
影响因子：
4.8
通讯作者：
Yamawaki, Hideyuki
中科院分区：
文献类型：
--
作者：
Usui, Tatsuya;Okada, Muneyoshi;Yamawaki, Hideyuki
真核延伸因子 2 激酶 (eEF2K) 是一种 Ca2+/钙调蛋白依赖性蛋白激酶。我们最近证明自发性高血压大鼠 (SHR) 肠系膜动脉中的 eEF2K 蛋白增加。高血压的发病机制部分受到血管炎症的调节。我们测试了 eEF2K 是否介导血管炎症反应和高血压发展的假设。在血管内皮细胞中，针对 eEF2K 的小干扰 RNA (siRNA) 可抑制 VCAM-1 和内皮选择素的诱导以及 TNF-α (10 ng/ml) 的单核细胞粘附。 eEF2K siRNA 抑制 JNK 和 NF-kappa B p65 的磷酸化以及 TNF-α 产生的活性氧 (ROS)。在血管平滑肌细胞中，eEF2K siRNA 还抑制 VCAM-1 诱导以及 TNF-α 对 JNK 和 NF-κ B 的磷酸化。在体内，eEF2K抑制剂NH125(500μg.kg(-1).day(-1))可降低SHR血压升高和ROS产生、炎症分子诱导以及SHR肠系膜上动脉肥大。在 SHR 肠系膜上动脉中，NH125 使乙酰胆碱诱导的舒张损伤正常化。目前的结果首次证明，eEF2K 通过 ROS 依赖性机制介导 TNF-α 诱导的血管炎症，这至少部分负责 SHR 高血压的发生。
Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca2+/calmodulin-dependent protein kinase. We recently demonstrated that eEF2K protein increases in mesenteric artery from spontaneously hypertensive rats (SHR). Pathogenesis of hypertension is regulated in part by vascular inflammation. We tested the hypothesis whether eEF2K mediates vascular inflammatory responses and development of hypertension. In vascular endothelial cells, small interfering RNA (siRNA) against eEF2K inhibited induction of VCAM-1 and endothelial-selectin as well as monocyte adhesion by TNF-alpha (10 ng/ml). eEF2K siRNA inhibited phosphorylation of JNK and NF-kappa B p65 as well as reactive oxygen species (ROS) production by TNF-alpha. In vascular smooth muscle cells, eEF2K siRNA also inhibited VCAM-1 induction and phosphorylation of JNK and NF-kappa B by TNF-alpha. In vivo, increased blood pressure in SHR and ROS production, induction of inflammatory molecules, and hypertrophy in SHR superior mesenteric artery were reduced by an eEF2K inhibitor NH125 (500 mu g.kg(-1).day(-1)). In SHR superior mesenteric artery, impairment of ACh-induced relaxation was normalized by NH125. The present results for the first time demonstrate that eEF2K mediates TNF-alpha-induced vascular inflammation via ROS-dependent mechanism, which is at least partly responsible for the development of hypertension in SHR.