Department of Systems Pharmacology and Translational Therapeutics and the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, Philadelphia, PA (E.R., S.Y.T., D.M., S.D.R., H.M., X.L., N.F.L., A.M.W., G.A.F.).
Department of Biochemistry, Cambridge Systems Biology Centre, University of Cambridge, United Kingdom (C.C., W.T.E.B., J.A.W., J.L.G.).
Circulation. 2018 Nov 20;138(21):2367-2378. doi: 10.1161/CIRCULATIONAHA.118.033540.
Large-scale, placebo-controlled trials established that nonsteroidal anti-inflammatory drugs confer a cardiovascular hazard: this has been attributed to depression of cardioprotective products of cyclooxygenase (COX)-2, especially prostacyclin. An alternative mechanism by which nonsteroidal anti-inflammatory drugs might constrain cardioprotection is by enhancing the formation of methylarginines in the kidney that would limit the action of nitric oxide throughout the vasculature.
Targeted and untargeted metabolomics were used to investigate the effect of COX-2 deletion or inhibition in mice and in osteoarthritis patients exposed to nonsteroidal anti-inflammatory drugs on the l-arginine/nitric oxide pathway.
Analysis of the plasma and renal metabolome was performed in postnatal tamoxifen-inducible Cox-2 knockout mice, which exhibit normal renal function and blood pressure. This revealed no changes in arginine and methylarginines compared with their wild-type controls. Moreover, the expression of genes in the l-arginine/nitric oxide pathway was not altered in the renal medulla or cortex of tamoxifen inducible Cox-2 knockout mice. Therapeutic concentrations of the selective COX-2 inhibitors, rofecoxib, celecoxib, and parecoxib, none of which altered basal blood pressure or renal function as reflected by plasma creatinine, failed to elevate plasma arginine and methylarginines in mice. Finally, plasma arginine or methylarginines were not altered in osteoarthritis patients with confirmed exposure to nonsteroidal anti-inflammatory drugs that inhibit COX-1 and COX-2. By contrast, plasma asymmetrical dimethylarginine was increased in mice infused with angiotensin II sufficient to elevate blood pressure and impair renal function. Four weeks later, blood pressure, plasma creatinine, and asymmetrical dimethylarginine were restored to normal levels. The increase in asymmetrical dimethylarginine in response to infusion with angiotensin II in celecoxib-treated mice was also related to transient impairment of renal function.
Plasma methylarginines are not altered by COX-2 deletion or inhibition but rather are elevated coincident with renal compromise.
大规模、安慰剂对照试验证实，非甾体抗炎药会带来心血管风险：这归因于环氧化酶 (COX)-2 的保护性产物，特别是前列腺素的抑制。非甾体抗炎药可能通过增强肾脏中甲基精氨酸的形成来限制心血管保护作用的另一种机制，从而限制整个血管系统中一氧化氮的作用。
使用靶向和非靶向代谢组学方法研究 COX-2 缺失或抑制对暴露于非甾体抗炎药的小鼠和骨关节炎患者的 l-精氨酸/一氧化氮途径的影响。
在出生后用他莫昔芬诱导的 Cox-2 敲除小鼠中进行了血浆和肾脏代谢组学分析，这些小鼠表现出正常的肾功能和血压。与野生型对照相比，它们的精氨酸和甲基精氨酸没有变化。此外，在他莫昔芬诱导的 Cox-2 敲除小鼠的肾髓质或皮质中，l-精氨酸/一氧化氮途径的基因表达没有改变。治疗浓度的选择性 COX-2 抑制剂罗非昔布、塞来昔布和帕瑞昔布，都没有改变基础血压或反映血浆肌酐的肾功能，也未能提高小鼠的血浆精氨酸和甲基精氨酸水平。最后，在经证实暴露于抑制 COX-1 和 COX-2 的非甾体抗炎药的骨关节炎患者中，血浆精氨酸或甲基精氨酸没有改变。相比之下，在给予足够升高血压和损害肾功能的血管紧张素 II 的小鼠中，血浆不对称二甲基精氨酸增加。四周后，血压、血浆肌酐和不对称二甲基精氨酸恢复正常水平。在接受塞来昔布治疗的小鼠中，给予血管紧张素 II 后不对称二甲基精氨酸的增加也与肾功能短暂受损有关。
血浆甲基精氨酸不受 COX-2 缺失或抑制的影响，而是在肾功能受损时升高。
