Oxidative stress-dependent cyclooxygenase-2-derived prostaglandin f(2α) impairs endothelial function in renovascular hypertensive rats.
Oxidative stress-dependent cyclooxygenase-2-derived prostaglandin f(2α) impairs endothelial function in renovascular hypertensive rats.
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DOI：
10.1089/ars.2010.3874
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发表时间：
2012-02
影响因子：
6.6
通讯作者：
X. Tian;W. Wong;F. Leung;Yang Zhang;Yi-xiang Wang;H. Lee;C. Ng;Z. Chen;X. Yao;C. Au
中科院分区：
文献类型：
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作者：
X. Tian;W. Wong;F. Leung;Yang Zhang;Yi-xiang Wang;H. Lee;C. Ng;Z. Chen;X. Yao;C. Au
摘要目的：内皮源性收缩因子（EDCFs）在肾血管性高血压（RH）中调节肾血管功能的作用尚未阐明。本研究旨在探讨氧化应激依赖性环氧化酶(COX)-2衍生的前列腺素F(2α) （PGF(2α)）是否会损害肾血管性高血压大鼠（RHR）肾动脉内皮功能。结果采用双肾双夹模型，双肾动脉狭窄致大鼠肾性高血压。急性治疗时使用活性氧（ROS）清除剂、COX-2抑制剂和血栓素-前列腺素受体拮抗剂，但不使用COX-1抑制剂，可改善RHR肾动脉内皮依赖性松弛和消除内皮依赖性收缩。塞来昔布或tempol治疗5周后，降低了rrr患者的血压，增加了肾血流量，并恢复了内皮功能。RHR动脉中ROS生成的增加被ROS清除剂抑制，但不受COX-2抑制剂的影响；而ROS清除剂和COX-2抑制剂均可减少PGF（2α）的释放。ROS还诱导RHR肾动脉cox -2依赖性收缩，并伴有cox -2衍生的PGF（2α）的释放。此外，慢性tempol治疗降低了RHR肾动脉中COX-2和BMP4上调、p38MAPK磷酸化和硝基酪氨酸水平。结论氧化应激可引发COX-2活性升高，而COX-2衍生的PGF（2α）在RH中介导内皮功能障碍中发挥重要作用。因此，目前的研究表明，靶向氧化应激依赖性cox -2衍生PGF（2α）的药物可能有助于RH的预防和治疗。Antioxid。机械工程学报，36(2):363-373。
UNLABELLED Abstract Aims: The role of endothelium-derived contracting factors (EDCFs) in regulating renovascular function is yet to be elucidated in renovascular hypertension (RH). The current study investigated whether oxidative stress-dependent cyclooxygenase (COX)-2-derived prostaglandin F(2α) (PGF(2α)) impairs endothelial function in renal arteries of renovascular hypertensive rats (RHR). RESULTS Renal hypertension was induced in rats by renal artery stenosis of both kidneys using the 2-kidney 2-clip model. Acute treatment with reactive oxygen species (ROS) scavengers, COX-2 inhibitors, and thromboxane-prostanoid receptor antagonists, but not COX-1 inhibitors, improved endothelium-dependent relaxations and eliminated endothelium-dependent contractions in RHR renal arteries. Five weeks of treatment with celecoxib or tempol reduced blood pressure, increased renal blood flow, and restored endothelial function in RHRs. Increased ROS production in RHR arteries was inhibited by ROS scavengers, but unaffected by COX-2 inhibitors; whereas increased PGF(2α) release was reduced by both ROS scavengers and COX-2 inhibitors. ROS also induced COX-2-dependent contraction in RHR renal arteries, which was accompanied by the release of COX-2-derived PGF(2α). Further, chronic tempol treatment reduced COX-2 and BMP4 upregulation, p38MAPK phosphorylation, and the nitrotyrosine level in RHR renal arteries. CONCLUSION These findings demonstrate the functional importance of oxidative stress, which serves as an initiator of increased COX-2 activity, and that COX-2-derived PGF(2α) plays an important role in mediating endothelial dysfunction in RH. INNOVATION The current study, thus, suggests that drugs targeting oxidative stress-dependent COX-2-derived PGF(2α) may be useful in the prevention and management of RH. Antioxid. Redox Signal. 16, 363-373.