C-reactive protein inhibits endothelium-dependent NO-mediated dilation in coronary arterioles by activating p38 kinase and NAD(P)H oxidase
C-reactive protein inhibits endothelium-dependent NO-mediated dilation in coronary arterioles by activating p38 kinase and NAD(P)H oxidase
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DOI：
10.1161/01.atv.0000159890.10526.1e
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发表时间：
2005-05-01
影响因子：
8.7
通讯作者：
Hein, TW
中科院分区：
文献类型：
--
作者：
Qamirani, E;Ren, Y;Hein, TW
C-反应蛋白（CRP）是一种促炎性标志物，其水平升高与冠状动脉疾病患者全身内皮依赖性NO介导的舒张功能降低相关;然而，CRP对冠状动脉微血管反应性的直接影响尚不清楚。在此，我们研究了CRP是否可以调节内皮依赖性NO介导的冠状小动脉扩张和是否促炎信号通路，如应激活化蛋白激酶（p38和c-Jun N-末端激酶[JNK]）和氧化应激参与CRP介导的effect.Methods和Results-Porcine冠状小动脉分离和加压无流量体外研究。用临床相关浓度的CRP（7 μ g/mL; 1小时）进行腔内治疗显著减弱了NO释放和对5-羟色胺的血管舒张。进一步与NO前体L-精氨酸（3 mmol/L）孵育，部分恢复了阿托伐他汀诱导的血管舒张。在存在超氧化物清除剂4-羟基-2，2，6，6-四甲基哌啶-1-氧基（TEMPOL）、NAD（P）H氧化酶抑制剂apocynin或p38激酶（NAD（P）H氧化酶的上游激活剂）抑制剂SB 203850的情况下，但不存在黄嘌呤氧化酶抑制剂别嘌呤醇或JNK抑制剂SP 600125，CRP对apocynin诱导的扩张的不利影响被阻止。二氢乙锭染色显示，CRP产生SB 203850和TEMPO敏感的超氧化物在小动脉内皮细胞的生产。CRP治疗的冠状动脉显着增加NAD（P）H氧化酶activity.Conclusions-CRP抑制内皮依赖性NO介导的扩张冠状动脉NAD（P）H氧化酶通过p38激酶激活产生超氧化物。通过损害内皮依赖性NO介导的血管反应性，CRP可以促进许多心血管疾病的发生。
Objective-Elevated levels of C-reactive protein (CRP), a proinflammatory marker, are associated with reduced systemic endothelium-dependent NO-mediated dilation in patients with coronary artery disease; however, the direct effect of CRP on coronary microvascular reactivity remains unknown. Herein, we examined whether CRP can modulate endothelium-dependent NO-mediated dilation of coronary arterioles and whether proinflammatory signaling pathways such as stress-activated protein kinases (p38 and c-Jun N-terminal kinase [JNK]) and oxidative stress are involved in the CRP-mediated effect.Methods and Results-Porcine coronary arterioles were isolated and pressurized without flow for in vitro study. Intraluminal treatment with a clinically relevant concentration of CRP (7 mu g/mL; 1 hour) significantly attenuated the NO release and vasodilation to serotonin. Further incubation with the NO precursor L-arginine (3 mmol/L) partially restored serotonin-induced vasodilation. In the presence of superoxide scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL), NAD(P)H oxidase inhibitor apocynin, or p38 kinase (an upstream activator of NAD( P) H oxidase) inhibitor SB203850, but not xanthine oxidase inhibitor allopurinol or JNK inhibitor SP600125, the detrimental effect of CRP on serotonin-induced dilation was prevented. Dihydroethidium staining showed that CRP produced SB203850- and TEMPOL-sensitive superoxide production in the arteriolar endothelium. CRP treatment of coronary arterioles significantly increased NAD(P)H oxidase activity.Conclusions-CRP inhibits endothelium-dependent NO-mediated dilation in coronary arterioles by producing superoxide from NAD(P)H oxidase via p38 kinase activation. By impairing endothelium-dependent NO-mediated vasoreactivity, CRP could facilitate the initiation of numerous cardiovascular diseases.