Lin Rong, Liu Juntian, Gan Weijie, Yang Guangde
Department of Pharmacology, Medical School of Xi'an Jiaotong University, PR China.
Biol Pharm Bull. 2004 Oct;27(10):1537-43. doi: 10.1248/bpb.27.1537.
Inflammation plays a pivotal role in the formation of atherosclerosis. In addition to being a risk marker for cardiovascular diseases, the role of C-reactive protein (CRP) in atherogenesis has been supported by more recent data. CD40-CD40L system is proven to be an important mediator of several auto-immune and chronic inflammation diseases. Interruption of CD40-CD40L signaling pathway not only reduces the initiation and progression of atherosclerotic lesions, but also modulates plaque architecture. By using a flow cytometry and western blotting, we found that incubation of human umbilical vein endothelial cells (HUVECs) with CRP resulted in a time- and dose-dependent increase in the cell-surface expression of CD40 and CD40L. In addition, CRP (25 microg/ml) increased gelatinolytic activities of MMP-2 and MMP-9. Anti-CD40 antibody significantly reversed the upregulated activities of MMP-2 and MMP-9 induced by CRP with gelatin zymography. Furthermore, lovastatin (10(-7), 10(-6), 10(-5) mol/l) and fenofibrate (5 x 10(-5), 10(-4), 2 x 10(-4) mol/l) significantly diminished the expression of CD40, CD40L and gelatinase activities (MMP-2, MMP-9) induced by CRP in HUVECs. In conclusion, our data provide evidence to support the direct pro-inflammatory effects of CRP via CD40-CD40L signaling pathway involved in the pathogenesis of atherosclerosis, and lovastatin and fenofibrate possess anti-inflammatory effects independent of their lipid-lowering action.
炎症在动脉粥样硬化的形成中起关键作用。除了作为心血管疾病的风险标志物外，C反应蛋白（CRP）在动脉粥样硬化发生中的作用也得到了最新数据的支持。CD40-CD40L系统被证明是几种自身免疫性和慢性炎症性疾病的重要介质。CD40-CD40L信号通路的中断不仅能减少动脉粥样硬化病变的起始和进展，还能调节斑块结构。通过流式细胞术和蛋白质印迹法，我们发现用CRP孵育人脐静脉内皮细胞（HUVECs）会导致CD40和CD40L的细胞表面表达呈时间和剂量依赖性增加。此外，CRP（25微克/毫升）增加了MMP-2和MMP-9的明胶酶活性。抗CD40抗体通过明胶酶谱法显著逆转了CRP诱导的MMP-2和MMP-9活性上调。此外，洛伐他汀（10^-7、10^-6、10^-5摩尔/升）和非诺贝特（5×10^-5、10^-4、2×10^-4摩尔/升）显著降低了CRP在HUVECs中诱导的CD40、CD40L表达和明胶酶活性（MMP-2、MMP-9）。总之，我们的数据提供了证据，支持CRP通过参与动脉粥样硬化发病机制的CD40-CD40L信号通路产生直接促炎作用，并且洛伐他汀和非诺贝特具有独立于其降脂作用的抗炎作用。
