C-Reactive Protein Induces Release of Both Endothelial Microparticles and Circulating Endothelial Cells In Vitro and In Vivo: Further Evidence of Endothelial Dysfunction
C-Reactive Protein Induces Release of Both Endothelial Microparticles and Circulating Endothelial Cells In Vitro and In Vivo: Further Evidence of Endothelial Dysfunction
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DOI：
10.1373/clinchem.2011.169839
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发表时间：
2011-12-01
影响因子：
9.3
通讯作者：
Jialal, Ishwarlal
中科院分区：
文献类型：
--
作者：
Devaraj, Sridevi;Kumaresan, Pappanaicken R.;Jialal, Ishwarlal
背景：炎症在动脉粥样硬化中起关键作用。动脉粥样硬化的一个关键早期事件是内皮功能障碍。C反应蛋白(CRP)是人类炎症的典型标记物，是心血管疾病的危险标记物，越来越多的证据支持其在动脉粥样硬化血栓形成中的作用。C反应蛋白在体外和体内都被证明能促进内皮功能障碍。新出现的内皮功能障碍的生物标志物包括循环内皮细胞(CECs)和内皮微粒(EMPs)。然而，在体内外研究CRP对CEC和EMP产生的影响的数据很少。方法：在本报告中，我们用不同浓度的CRP(0-50µg/mL)或煮熟的CRP处理人主动脉内皮细胞。结果：尽管CRP治疗后CECs和EMPs的释放均显著增加，但煮沸的CRP不能起到作用。用保留一氧化氮(NO)的Sepiapterin或二乙烯三胺NONOate预处理HAECs，可减弱CRP对CECs和EMPs的作用。CD32和CD64封闭抗体，但不能阻止CD16抗体或氧化型低密度脂蛋白受体1小干扰RNA(LOX-1 siRNA)抑制CRP诱导的CECs和EMPs的产生。此外，与人血清白蛋白相比，给Wistar大鼠注射人CRP导致CECs和EMPs显著增加，证实了体外研究结果。结论：我们提供了新的数据，即CRP通过NO缺乏，通过诱导内皮功能障碍的生物标志物CECs和EMPs的释放而促进内皮功能障碍。(C)2011年美国临床化学协会
BACKGROUND: Inflammation is pivotal in atherosclerosis. A key early event in atherosclerosis is endothelial dysfunction. C-reactive protein (CRP), the prototypic marker of inflammation in humans, is a risk marker for cardiovascular disease, and there is mounting evidence to support its role in atherothrombosis. CRP has been shown to promote endothelial dysfunction both in vitro and in vivo. Emerging biomarkers of endothelial dysfunction include circulating endothelial cells (CECs) and endothelial microparticles (EMPs). However, there is a paucity of data examining the effect of CRP on CEC and EMP production in vitro and in vivo.METHODS: In this report, we treated human aortic endothelial cells (HAECs) with increasing concentrations of CRP (0-50 mu g/mL) or boiled CRP. We counted CECs and EMPs by flow cytometry.RESULTS: Although CRP treatment resulted in a significant increase in release of both CECs and EMPs, boiled CRP failed to have an effect. Pretreatment of HAECs with sepiapterin or diethylenetriamine NONOate, both of which preserve nitric oxide (NO), resulted in attenuation of CRP's effects on CECs and EMPs. CD32 and CD64 blocking antibodies but not CD16 antibody or lectin-like oxidized LDL receptor 1 small interfering RNA (LOX-1 siRNA) prevented CRP-induced production of CECs and EMPs. Furthermore, delivery of human CRP to Wistar rats compared with human serum albumin resulted in significantly increased CECs and EMPs, corroborating the in vitro findings.CONCLUSIONS: We provide novel data that CRP, via NO deficiency, promotes endothelial dysfunction by inducing release of CECs and EMPs, which are biomarkers of endothelial dysfunction. (C) 2011 American Association for Clinical Chemistry