Interleukin-17 causes Rho-kinase-mediated endothelial dysfunction and hypertension
Interleukin-17 causes Rho-kinase-mediated endothelial dysfunction and hypertension
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DOI：
10.1093/cvr/cvs422
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发表时间：
2013-03-15
影响因子：
10.8
通讯作者：
Mitchell, Brett M.
中科院分区：
文献类型：
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作者：
Hoanglan Nguyen;Chiasson, Valorie L.;Mitchell, Brett M.
促炎细胞因子白细胞介素- 17a （IL-17）水平升高与高血压自身免疫性疾病相关然而，IL-17与高血压之间的关系尚不清楚。我们假设IL-17通过降低内皮细胞一氧化氮的产生而升高血压。IL-17急性处理内皮细胞导致抑制内皮一氧化氮（NO）合成酶残基苏氨酸495 （eNOS Thr495）磷酸化显著增加。在已知的磷酸化eNOS Thr495的激酶中，只有抑制rho激酶才能阻止il -17诱导的增加。IL-17导致rho激酶激活剂RhoA增加三倍，而这被IL-17中和抗体所阻止。在离体小鼠主动脉中，IL-17显著增加eNOS Thr495磷酸化，诱导RhoA表达，减少no依赖性松弛反应，所有这些都可以通过IL-17中和抗体或抑制RhoA激酶来阻止。在小鼠中，IL-17治疗1周显著增加收缩压，这与主动脉no依赖性松弛反应降低、eNOS Thr495磷酸化增加和RhoA表达增加有关。抑制rho激酶可预防IL-17引起的高血压。这些数据表明，IL-17激活RhoA/ rho激酶导致内皮功能障碍和高血压。IL-17或rho激酶抑制剂可能被证明是IL-17相关自身免疫性疾病的降压药物。
Elevated levels of pro-inflammatory cytokine interleukin-17A (IL-17) are associated with hypertensive autoimmune diseases; however, the connection between IL-17 and hypertension is unknown. We hypothesized that IL-17 increases blood pressure by decreasing endothelial nitric oxide production.Acute treatment of endothelial cells with IL-17 caused a significant increase in phosphorylation of the inhibitory endothelial nitric oxide (NO) synthase residue threonine 495 (eNOS Thr495). Of the kinases known to phosphorylate eNOS Thr495, only inhibition of Rho-kinase prevented the IL-17-induced increase. IL-17 caused a threefold increase in the Rho-kinase activator RhoA, and this was prevented by an IL-17 neutralizing antibody. In isolated mouse aortas, IL-17 significantly increased eNOS Thr495 phosphorylation, induced RhoA expression, and decreased NO-dependent relaxation responses, all of which were prevented by either an IL-17 neutralizing antibody or inhibition of Rho-kinase. In mice, IL-17 treatment for 1 week significantly increased systolic blood pressure and this was associated with decreased aortic NO-dependent relaxation responses, increased eNOS Thr495 phosphorylation, and increased RhoA expression. Inhibition of Rho-kinase prevented the hypertension caused by IL-17.These data demonstrate that IL-17 activates RhoA/Rho-kinase leading to endothelial dysfunction and hypertension. Inhibitors of IL-17 or Rho-kinase may prove useful as anti-hypertensive drugs in IL-17-associated autoimmune diseases.