C-reactive protein induces VCAM-1 gene expression through NF-kappaB activation in vascular endothelial cells.
Recent studies have shown that C-reactive protein (CRP) is not just a predictor of cardiovascular events but also acts directly as a proinflammatory stimulus in vascular cells. In this report, we studied the molecular mechanisms underlying vascular cellular adhesion molecule-1 (VCAM-1) induction by CRP. CRP-induced VCAM-1 mRNA expression and this induction was inhibited by protein kinase C (PKC) inhibitors, p38 mitogen-activated protein kinase (MAPK) inhibitor, and tyrosine kinase inhibitors. In addition, parthenolide, a nuclear factor kappaB (NF-kappaB) inhibitor, abolished VCAM-1 induction. Moreover, CRP increased VCAM-1 promoter activity, indicating that CRP induces VCAM-1 mRNA expression at the transcriptional level. Mutation of NF-kappaB-binding sites resulted in a loss of induction. Finally, an electrophoretic mobility shift assay confirmed binding of the p65 subunit of NF-kappaB to kappaB-binding sites. Taken together, our findings suggest that VCAM-1 induction by CRP is mediated by PKC, p38MAPK, tyrosine kinase and the NF-kappaB-dependent signaling pathways in vascular endothelial cells.
Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
Daiji
D
Kawanami
Koji
K
Maemura
Norihiko
N
Takeda
Tomohiro
T
Harada
Takefumi
T
Nojiri
Tetsuya
T
Saito
Ichiro
I
Manabe
Yasushi
Y
Imai
Ryozo
R
Nagai
D000818:Animals; D001011:Aorta / Q000166:cytology; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015152:Blotting, Northern; D002097:C-Reactive Protein / Q000494:pharmacology*; D002417:Cattle; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics*
D016328:NF-kappa B; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; D002097:C-Reactive Protein