Wu Jianbo, Stevenson Meredith J, Brown Jordan M, Grunz Elizabeth A, Strawn Tammy L, Fay William P
Department of Internal Medicine, University of Missouri School of Medicine, and Research Service, Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, MO 65212, USA.
Arterioscler Thromb Vasc Biol. 2008 Apr;28(4):698-704. doi: 10.1161/ATVBAHA.107.160903. Epub 2008 Feb 14.
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).
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.
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.
我们研究了C反应蛋白（CRP）对血管平滑肌细胞（VSMC）组织因子（TF）和TF途径抑制剂（TFPI）表达的影响。
从CRP转基因（Tg）小鼠分离的VSMC中，TF mRNA、蛋白和活性水平显著高于野生型（WT）小鼠。与WT VSMC相比，CRP-Tg VSMC中TFPI表达显著下调。用人CRP表达质粒转染人VSMC可显著增加TF表达并降低TFPI表达。Fcγ受体IIIa（FcγRIIIa）基因沉默可阻断CRP对VSMC TF表达的影响。CRP激活p44/42，但不激活p38或JNK丝裂原活化蛋白激酶（MAPK），且p44/42的药理学抑制剂可阻断CRP对TF表达的影响，而p38或JNK MAPK的抑制剂则不能。活性氧（ROS）清除剂可阻断CRP诱导的VSMC TF表达上调。体内分析显示，与WT小鼠相比，CRP-Tg小鼠颈动脉中TF表达显著增加，TFPI表达降低。
CRP在体外和体内均可增加VSMC的TF表达并降低TFPI表达。CRP诱导TF表达是由FcγRIIIa、p44/42 MAPK和ROS生成介导的。这些数据为CRP在动脉血栓形成发病机制中的作用提供了重要见解。
