C-reactive protein inhibits endothelium-dependent nitric oxide-mediated dilation of retinal arterioles via enhanced superoxide production
C-reactive protein inhibits endothelium-dependent nitric oxide-mediated dilation of retinal arterioles via enhanced superoxide production
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DOI：
10.1167/iovs.07-1387
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发表时间：
2008-05-01
影响因子：
4.4
通讯作者：
Hein, Travis W.
中科院分区：
文献类型：
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作者：
Nagaoka, Taiji;Kuo, Lih;Hein, Travis W.
目的。 C 反应蛋白 (CRP)（一种促炎标志物）水平升高与全身血管疾病相关。此外，临床研究表明，CRP 升高是糖尿病视网膜病变和年龄相关性黄斑变性的独立危险因素。然而，CRP 对眼部微血管反应性的直接影响仍不清楚。作者研究了 CRP 是否可以影响内皮依赖性一氧化氮 (NO) 介导的视网膜小动脉扩张，以及氧化应激和不同的蛋白激酶信号通路是否参与 CRP 介导的作用。方法。分离猪视网膜小动脉（内径，71+/-2μm）并在不流动的情况下加压用于体外研究。使用视频显微技术记录直径变化。二氢乙锭（DHE）用于检测超氧化物的产生。结果。使用临床相关浓度的 CRP（7 μg/mL，60 分钟）进行管腔内治疗可显着减弱内皮依赖性 NO 介导的激动剂缓激肽和 A23187 的小动脉扩张，但不会减弱内皮依赖性 NO 供体硝普钠的扩张作用。在存在超氧化物清除剂 TEMPOL、NAD(P)H 氧化酶抑制剂夹竹桃麻素、p38 激酶抑制剂 SB203580、辛伐他汀或 Rho 激酶抑制剂 Y-27632 的情况下，可以防止 CRP 对缓激肽诱导的扩张的不利影响。 DHE 染色显示 CRP 在小动脉内皮细胞中产生 TEMPOL 敏感的超氧化物。结论。 CRP 通过 NAD(P)H 氧化酶产生超氧化物来抑制视网膜小动脉中内皮依赖性 NO 介导的扩张，这似乎与 p38 激酶和 RhoA/Rho 激酶激活有关。通过损害内皮依赖性 NO 介导的血管反应性，CRP 可能会促进视网膜血管疾病的发展。此外，他汀类药物通过保护内皮功能（可能是通过灭活 RhoA/Rho 激酶途径）而有益。
PURPOSE. Elevated levels of C-reactive protein (CRP), a proinflammatory marker, are associated with systemic vascular disorders. In addition, clinical studies have implicated that elevated CRP is an independent risk factor for diabetic retinopathy and age-related macular degeneration. However, the direct effect of CRP on ocular microvascular reactivity remains unknown. The authors examined whether CRP can affect endothelium-dependent nitric oxide (NO)-mediated dilation of retinal arterioles and whether oxidative stress and distinct protein kinase signaling pathways are involved in the CRP-mediated effect.METHODS. Porcine retinal arterioles (internal diameter, 71 +/- 2 mu m) were isolated and pressurized without flow for in vitro study. Diameter changes were recorded using videomicroscopic techniques. Dihydroethidium (DHE) was used to detect superoxide production.RESULTS. Intraluminal treatment with a clinically relevant concentration of CRP (7 mu g/mL, 60 minutes) significantly attenuated arteriolar dilation to endothelium-dependent NO-mediated agonists bradykinin and A23187 but not to endothelium-independent NO donor sodium nitroprusside. In the presence of superoxide scavenger TEMPOL, NAD(P)H oxidase inhibitor apocynin, p38 kinase inhibitor SB203580, simvastatin, or Rho-kinase inhibitor Y-27632, the detrimental effect of CRP on bradykinin-induced dilation was prevented. DHE staining showed that CRP produced TEMPOL-sensitive superoxide production in the arteriolar endothelium.CONCLUSIONS. CRP inhibits endothelium-dependent NO-mediated dilation in retinal arterioles by producing superoxide from NAD(P)H oxidase, which appears to be linked with p38 kinase and RhoA/Rho-kinase activation. By impairing endothelium-dependent NO-mediated vasoreactivity, CRP can potentially facilitate the development of retinal vascular diseases. In addition, statins are beneficial by preserving endothelial function, possibly through inactivation of the RhoA/Rho-kinase pathway.