C-reactive protein enhances tissue factor expression by vascular smooth muscle cells: mechanisms and in vivo significance.
OBJECTIVE
We examined the impact of C-reactive protein (CRP) on vascular smooth muscle cell (VSMC) expression of tissue factor (TF) and TF pathway inhibitor (TFPI).


RESULTS
TF mRNA, protein, and activity levels were significantly higher in VSMCs isolated from CRP-transgenic (Tg) mice than from wild-type (WT) mice. TFPI expression was significantly downregulated in CRP-Tg versus WT VSMCs. Transfection of human VSMCs with CRP expression plasmid significantly increased TF expression and decreased TFPI expression. Gene silencing of Fc gamma receptor IIIa (Fc gammaRIIIa) blocked the effect of CRP on VSMC TF expression. CRP activated p44/42, but not p38 or JNK MAP kinase (MAPK), and the effect of CRP on TF expression was blocked by pharmacological inhibitor of p44/42, but not p38 or JNK MAPK. Reactive oxygen species (ROS) scavengers blocked CRP-induced upregulation of VSMC TF expression. In vivo analyses revealed significant increases in TF expression and decreases in TFPI expression in carotid arteries of CRP-Tg mice versus WT mice.


CONCLUSIONS
CRP increases TF and decreases TFPI expression by VSMCs in vitro and in vivo. Induction of TF expression by CRP is mediated by Fc gammaRIIIa, p44/42 MAPK, and ROS generation. These data offer important insights into the role of CRP in the pathogenesis of arterial thrombosis.
Wu
Jianbo
J
Department of Internal Medicine, University of Missouri School of Medicine, and Research Service, Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, MO 65212, USA. wuji@health.missouri.edu
Stevenson
Meredith J
MJ
Brown
Jordan M
JM
Grunz
Elizabeth A
EA
Strawn
Tammy L
TL
Fay
William P
WP
D000818:Animals; D001483:Base Sequence; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000209:etiology / Q000378:metabolism; D002339:Carotid Arteries / Q000166:cytology / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000235:genetics; D017452:Receptors, IgG / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D017931:DNA Primers; D008074:Lipoproteins; D034741:RNA, Small Interfering; D017452:Receptors, IgG; C051928:lipoprotein-associated coagulation inhibitor; D002097:C-Reactive Protein; D013925:Thromboplastin