Calcitriol protects renovascular function in hypertension by down-regulating angiotensin II type 1 receptors and reducing oxidative stress
Calcitriol protects renovascular function in hypertension by down-regulating angiotensin II type 1 receptors and reducing oxidative stress
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DOI：
10.1093/eurheartj/ehr459
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发表时间：
2012-12-01
影响因子：
39.3
通讯作者：
Huang, Yu
中科院分区：
文献类型：
--
作者：
Dong, Jinghui;Wong, Siu Ling;Huang, Yu
目的 本研究调查骨化三醇（维生素 D 的一种活性形式）是否可以预防高血压患者的肾血管功能障碍，如果可以，这种保护作用是否会改变参与该功能障碍的关键蛋白的表达。 方法和结果 等长张力的变化表明，在体外用骨化三醇治疗 12 小时，高血压患者肾动脉中受损的内皮依赖性舒张功能得到增强。二氢乙锭荧光显示这些动脉中活性氧（ROS）水平升高，而骨化三醇则降低了活性氧水平。免疫荧光显示骨化三醇处理降低了AT(1)R、NOX-2、NOX-4和p67(phox)的表达，并增加了超氧化物歧化酶(SOD)-1的表达。暴露于骨化三醇 12 小时可防止血压正常患者肾动脉中血管紧张素 (Ang) II 诱导的 ROS 增加以及肾动脉中 NOX-2、NOX-4 和 p67(phox) 的过度表达。人类维生素 D 受体 (VDR) 的特异性拮抗剂 TEI-9647 消除了骨化三醇的这些作用。体外暴露于骨化三醇以及长期体内施用骨化三醇均增强了乙酰胆碱的松弛，并消除了预先暴露于Ang II的正常血压大鼠或从自发性高血压大鼠（SHR）收获的肾动脉中过度的内皮依赖性收缩。通过骨化三醇的长期治疗，SHR动脉中的活性氧水平和AT(1)R、NAD(P)H氧化酶亚基、SOD-1和SOD-2的表达得以正常化。结论用骨化三醇在体内和体外激活VDR可以通过使AT(1)R以及自由基生成和清除酶的表达正常化来改善内皮功能，从而防止ROS过量产生。目前的研究结果表明，骨化三醇可有效保护高血压患者的内皮功能。
Aims The present study investigated whether or not calcitriol, an active form of vitamin D, protects against renovascular dysfunction in hypertension and, if so, whether or not such protection alters the expression of key proteins involved in that dysfunction.Methods and results Changes in isometric tension showed that the impaired endothelium-dependent relaxations in renal arteries of hypertensive patients were enhanced by 12 h in vitro treatment with calcitriol. Dihydroethidium fluorescence revealed an elevated level of reactive oxygen species (ROS) in these arteries which was reduced by calcitriol. Immunofluorescence showed that calcitriol treatment reduced the expression of AT(1)R, NOX-2, NOX-4, and p67(phox) and increased that of superoxide dismutase (SOD)-1. Twelve-hour exposure to calcitriol prevented angiotensin (Ang) II-induced increases in ROS and the over-expression of NOX-2, NOX-4, and p67(phox) in renal arteries from normotensive patients. A specific antagonist of the human vitamin D receptor (VDR), TEI-9647, abolished these effects of calcitriol. Both in vitro exposure to and chronic in vivo administration of calcitriol enhanced relaxations to acetylcholine and abolished exaggerated endothelium-dependent contractions in renal arteries of normotensive rats pre-exposed to Ang II or harvested from spontaneously hypertensive rats (SHR). Reactive oxygen species levels and expressions of AT(1)R, NAD(P)H oxidase subunits, SOD-1, and SOD-2 in SHR arteries were normalized by the chronic treatment with calcitriol.Conclusion In vivo and in vitro activation of VDR with calcitriol improves endothelial function by normalizing the expressions of AT(1)R and radical generating and scavenging enzymes and thus preventing ROS over-production. The present findings suggest that calcitriol is effective in preserving endothelial function in hypertension.