Verma Subodh, Li Shu-Hong, Badiwala Mitesh V, Weisel Richard D, Fedak Paul W M, Li Ren-Ke, Dhillon Bikramjit, Mickle Donald A G
Division of Cardiac Surgery, Toronto General Hospital Research Institute, University of Toronto, Canada.
Circulation. 2002 Apr 23;105(16):1890-6. doi: 10.1161/01.cir.0000015126.83143.b4.
C-reactive protein (CRP) has been suggested to actively participate in the development of atherosclerosis. In the present study, we examined the role of the potent endothelium-derived vasoactive factor endothelin-1 (ET-1) and the inflammatory cytokine interleukin-6 (IL-6) as mediators of CRP-induced proatherogenic processes.
Saphenous vein endothelial cells (HSVECs) were incubated with human recombinant CRP (25 microg/mL, 24 hours) and the expression of vascular cell adhesion molecule (VCAM-1), intracellular adhesion molecule (ICAM-1), and monocyte chemoattractant chemokine-1 was determined. The effects of CRP on LDL uptake were assessed in macrophages using immunofluorescent labeling of CD32 and CD14. In each study, the effect of endothelin antagonism (bosentan) and IL-6 inhibition (monoclonal anti-IL-6 antibodies) was examined. The effects of CRP on the secretion of ET-1 and IL-6 from HSVECs were also evaluated. Incubation of HSVECs with recombinant human CRP resulted in a marked increase in ICAM-1 and VCAM-1 expression (P<0.001). Likewise, CRP caused a significant increase in monocyte chemoattractant chemokine-1 production, a key mediator of leukocyte transmigration (P<0.001). CRP caused a marked and sustained increase in native LDL uptake by macrophages (P<0.05). These proatherosclerotic effects of CRP were mediated, in part, via increased secretion of ET-1 and IL-6 (P<0.01) and were attenuated by both bosentan and IL-6 antagonism (P<0.01).
CRP actively promotes a proatherosclerotic and proinflammatory phenotype. These effects are mediated, in part, via the production of ET-1 and IL-6 and are attenuated by mixed ET(A/B) receptor antagonism and IL-6 inhibition. Bosentan may be useful in decreasing CRP-mediated vascular disease.
有研究表明C反应蛋白（CRP）积极参与动脉粥样硬化的发展。在本研究中，我们检测了强效内皮源性血管活性因子内皮素-1（ET-1）和炎性细胞因子白细胞介素-6（IL-6）作为CRP诱导的促动脉粥样硬化过程介质的作用。
将大隐静脉内皮细胞（HSVECs）与人重组CRP（25μg/mL，24小时）共同孵育，检测血管细胞黏附分子（VCAM-1）、细胞间黏附分子（ICAM-1）和单核细胞趋化因子-1的表达。利用CD32和CD14的免疫荧光标记在巨噬细胞中评估CRP对低密度脂蛋白摄取的影响。在每项研究中，检测内皮素拮抗剂（波生坦）和IL-6抑制（抗IL-6单克隆抗体）的作用。还评估了CRP对HSVECs分泌ET-1和IL-6的影响。用重组人CRP孵育HSVECs导致ICAM-1和VCAM-1表达显著增加（P<0.001）。同样，CRP导致单核细胞趋化因子-1产生显著增加，单核细胞趋化因子-1是白细胞迁移的关键介质（P<0.001）。CRP导致巨噬细胞对天然低密度脂蛋白的摄取显著且持续增加（P<0.05）。CRP的这些促动脉粥样硬化作用部分通过增加ET-1和IL-6的分泌介导（P<0.01），并且被波生坦和IL-6拮抗作用减弱（P<0.01）。
CRP积极促进促动脉粥样硬化和促炎表型。这些作用部分通过ET-1和IL-6的产生介导，并且被ET（A/B）混合受体拮抗作用和IL-6抑制减弱。波生坦可能有助于降低CRP介导的血管疾病。
