Downregulation of Endothelial Transient Receptor Potential Vanilloid Type 4 Channel and Small-Conductance of Ca2+-Activated K+ Channels Underpins Impaired Endothelium-Dependent Hyperpolarization in Hypertension
Downregulation of Endothelial Transient Receptor Potential Vanilloid Type 4 Channel and Small-Conductance of Ca2+-Activated K+ Channels Underpins Impaired Endothelium-Dependent Hyperpolarization in Hypertension
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DOI：
10.1161/hypertensionaha.116.07110
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发表时间：
2017-01-01
期刊：
影响因子：
8.3
通讯作者：
Kitazono, Takanari
中科院分区：
文献类型：
--
作者：
Seki, Takunori;Goto, Kenichi;Kitazono, Takanari
内皮依赖性超极化（EDH）介导的反应在高血压中受损，但潜在的机制尚未确定。Ca2+激活的K+通道（SKCa和IKCa）的小电导和中电导的激活支持edh介导的反应。最近有报道称，Ca2+通过内皮瞬时受体电位香草样蛋白4通道（TRPV4）内流是特定床层内皮细胞中SKCa/IKCa激活的先决条件。在这里，我们试图通过20周龄卒中易发自发性高血压大鼠（SHRSP）和年龄匹配的Wistar-Kyoto大鼠（WKY）分离的系膜上动脉来确定高血压患者的EDH损伤是否归因于TRPV4和S/IKCa功能障碍。在WKY动脉中，联合使用SKCa/IKCa阻滞剂（apamin + TRAM-34; 1-[（2-氯苯基）二苯基甲基]- 1h -吡唑）和选择性拮抗剂RN-1734或HC-067047阻断TRPV4可降低edh介导的反应。与WKY相比，在SHRSP动脉中，edh介导的超极化和舒张明显受损。GSK1016790A是一种选择性TRPV4激活剂，在WKY动脉中引起了强大的超极化和舒张。相比之下，在SHRSP动脉中，gsk1016790a诱发的超极化很小，没有松弛。选择性SKCa激活剂环己基-[2-（3,5-二甲基吡唑-1-基）-6-甲基嘧啶-4-基]-胺的超极化和弛豫在SHRSP动脉中与WKY动脉相比略有降低。与WKY相比，SHRSP肠系膜动脉内皮细胞TRPV4和SKCa蛋白的表达明显降低，而IKCa的功能和表达在SHRSP动脉中得以保留。这些发现表明，由于TRPV4和SKCa对EDH的输入减少，SHRSP的肠系膜上动脉中EDH介导的反应受损。
Endothelium-dependent hyperpolarization (EDH)-mediated responses are impaired in hypertension, but the underlying mechanisms have not yet been determined. The activation of small- and intermediate-conductance of Ca2+-activated K+ channels (SKCa and IKCa) underpins EDH-mediated responses. It was recently reported that Ca2+ influx through endothelial transient receptor potential vanilloid type 4 channel (TRPV4) is a prerequisite for the activation of SKCa/IKCa in endothelial cells in specific beds. Here, we attempted to determine whether the impairment of EDH in hypertension is attributable to the dysfunction of TRPV4 and S/IKCa, using isolated superior mesenteric arteries of 20-week-old stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wistar-Kyoto (WKY) rats. In the WKY arteries, EDH-mediated responses were reduced by a combination of SKCa/IKCa blockers (apamin plus TRAM-34; 1-[(2-chlorophenyl)diphenylmethl]-1H-pyrazole) and by the blockade of TRPV4 with the selective antagonist RN-1734 or HC-067047. In the SHRSP arteries, EDH-mediated hyperpolarization and relaxation were significantly impaired when compared with WKY. GSK1016790A, a selective TRPV4 activator, evoked robust hyperpolarization and relaxation in WKY arteries. In contrast, in SHRSP arteries, the GSK1016790A-evoked hyperpolarization was small and relaxation was absent. Hyperpolarization and relaxation to cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine, a selective SKCa activator, were marginally decreased in SHRSP arteries compared with WKY arteries. The expression of endothelial TRPV4 and SKCa protein was significantly decreased in the SHRSP mesenteric arteries compared with those of WKY, whereas function and expression of IKCa were preserved in SHRSP arteries. These findings suggest that EDH-mediated responses are impaired in superior mesenteric arteries of SHRSP because of a reduction in both TRPV4 and SKCa input to EDH.