环氧化酶-2抑制作用可限制血管紧张素II诱导的人体DNA氧化和蛋白质硝化反应。
Cyclooxygenase-2 Inhibition Limits Angiotensin II-Induced DNA Oxidation and Protein Nitration in Humans.
作者信息
Pialoux Vincent, Poulin Marc J, Hemmelgarn Brenda R, Muruve Daniel A, Chirico Erica N, Faes Camille, Sola Darlene Y, Ahmed Sofia B
机构信息
Laboratoire Interuniversitaire de Biologie de la Motricité EA7424, Université de Lyon, Université Claude Bernard Lyon 1 Villeurbanne, France.
Faculty of Medicine, Hotchkiss Brain Institute, University of CalgaryCalgary, AB, Canada; Department of Physiology and Pharmacology, Faculty of Medicine, University of CalgaryCalgary, AB, Canada; Faculty of Medicine, Libin Cardiovascular Institute of Alberta, University of CalgaryCalgary, AB, Canada; Department of Clinical Neurosciences, Cumming School of Medicine, University of CalgaryCalgary, AB, Canada; Faculty of Kinesiology, University of CalgaryCalgary, AB, Canada.
出版信息
Front Physiol. 2017 Mar 10;8:138. doi: 10.3389/fphys.2017.00138. eCollection 2017.
Compared to other cyclooxygenase-2 inhibitors, celecoxib is associated with a lower cardiovascular risk, though the mechanism remains unclear. Angiotensin II is an important mediator of oxidative stress in the pathophysiology of vascular disease. Cyclooxygenase-2 may modify the effects of angiotensin II though this has never been studied in humans. The purpose of the study was to test the effects of selective cyclooxygenase-2 inhibition on plasma measures of oxidative stress, the vasoconstrictor endothelin-1, and nitric oxide metabolites, both at baseline and in respose to Angiotensin II challenge in healthy humans. Measures of 8-hydroxydeoxyguanosine, advanced oxidation protein products, nitrotyrosine, endothelin-1, and nitric oxide metabolites were assessed from plasma samples drawn at baseline and in response to graded angiotensin II infusion (3 ng/kg/min × 30 min, 6 ng/kg/min × 30 min) before and after 14 days of cyclooxygenase-2 inhibition in 14 healthy subjects (eight male, six female) in high salt balance, a state of maximal renin angiotensin system suppression. Angiotensin II infusion significantly increased plasma oxidative stress compared to baseline (8-hydroxydeoxyguanosine; +17%; advanced oxidation protein products; +16%), nitrotyrosine (+76%). Furthermore, levels of endothelin-1 levels were significantly increased (+115%) and nitric oxide metabolites were significantly decreased (-20%). Cycloxygenase-2 inhibition significantly limited the increase in 8-hydroxydeoxyguanosine, nitrotyrosine and the decrease in nitric oxide metabolites induced by angiotensin II infusion, though no changes in advanced oxidation protein products and endothelin-1 concentrations were observed. Cyclooxygenase-2 inhibition with celecoxib partially limited the angiotensin II-mediated increases in markers of oxidative stress in humans, offering a potential physiological pathway for the improved cardiovascular risk profile of this drug.
与其他环氧化酶 -2 抑制剂相比，塞来昔布与较低的心血管风险相关，但其机制尚不清楚。血管紧张素 II 是血管疾病病理生理学中氧化应激的重要介质。环氧化酶 -2 可能会改变血管紧张素 II 的作用，不过这从未在人体中进行过研究。本研究的目的是测试选择性环氧化酶 -2 抑制对健康人体血浆氧化应激指标、血管收缩剂内皮素 -1 和一氧化氮代谢产物的影响，包括在基线时以及对血管紧张素 II 激发的反应中。在 14 名处于高盐平衡（一种最大程度抑制肾素血管紧张素系统的状态）的健康受试者（8 名男性，6 名女性）中，在环氧化酶 -2 抑制 14 天前后，对基线时以及对分级血管紧张素 II 输注（3 ng/kg/分钟×30 分钟，6 ng/kg/分钟×30 分钟）反应时采集的血浆样本进行 8 - 羟基脱氧鸟苷、晚期氧化蛋白产物、硝基酪氨酸、内皮素 -1 和一氧化氮代谢产物的检测。与基线相比，血管紧张素 II 输注显著增加了血浆氧化应激（8 - 羟基脱氧鸟苷；增加 17%；晚期氧化蛋白产物；增加 16%）、硝基酪氨酸（增加 76%）。此外，内皮素 -1 水平显著升高（增加 115%），一氧化氮代谢产物显著降低（降低 20%）。环氧化酶 -2 抑制显著限制了血管紧张素 II 输注诱导的 8 - 羟基脱氧鸟苷、硝基酪氨酸的增加以及一氧化氮代谢产物的降低，不过未观察到晚期氧化蛋白产物和内皮素 -1 浓度的变化。用塞来昔布抑制环氧化酶 -2 部分限制了血管紧张素 II 介导的人体氧化应激标志物的增加，为该药物改善心血管风险状况提供了一条潜在的生理途径。
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