C-reactive protein-induced expression of CD40-CD40L and the effect of lovastatin and fenofibrate on it in human vascular endothelial cells.
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.
Department of Pharmacology, Medical School of Xi'an Jiaotong University, PR China. linrong@mail.xjtu.edu.cn
Rong
R
Lin
Juntian
J
Liu
Weijie
W
Gan
Guangde
G
Yang
D002097:C-Reactive Protein / Q000378:metabolism*; D019013:CD40 Antigens / Q000096:biosynthesis*; D023201:CD40 Ligand / Q000096:biosynthesis*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology*; D011345:Fenofibrate / Q000494:pharmacology*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D014470:Umbilical Cord / Q000166:cytology
D019013:CD40 Antigens; D000960:Hypolipidemic Agents; D061965:Matrix Metalloproteinase Inhibitors; D023201:CD40 Ligand; D002097:C-Reactive Protein; D008148:Lovastatin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D011345:Fenofibrate