Cardiovascular Research, Physiology Institute, University of Zurich, Zurich, Switzerland.
Basic Res Cardiol. 2010 May;105(3):349-56. doi: 10.1007/s00395-009-0060-0. Epub 2009 Oct 1.
Tissue factor (TF) is the principal trigger of the coagulation cascade and involved in arterial thrombus formation. Platelet-derived growth factor CC (PDGF-CC) is a recently discovered member of the PDGF family released upon platelet activation. This study assesses the impact of PDGF-CC on TF expression in human cells. PDGF-CC concentration-dependently induced TF expression by 2.5-fold in THP-1 cells, by 2.0-fold in human peripheral blood monocytes, by 1.4-fold in vascular smooth muscle cells, and by 2.6-fold in microvascular endothelial cells, but did not affect TF expression in aortic endothelial cells. A similar pattern was observed with PDGF-BB. In contrast, PDGF-AA did not alter TF expression in THP-1 cells. TF whole cell activity was induced following stimulation with PDGF-BB and PDGF-CC in THP-1 cells. Real-time polymerase chain reaction revealed that PDGF-CC induced TF mRNA. PDGF-CC transiently activated p42/44 MAP kinase [extracellular signal-regulated kinase (ERK)], while phosphorylation of the MAP kinases c-Jun NH(2)-terminal kinase (JNK) and p38 remained unaffected. PD98059, a specific inhibitor of ERK phosphorylation, but not the p38 inhibitor SB203580 or the JNK inhibitor SP600125 prevented PDGF-CC induced TF expression in a concentration-dependent manner. The effect of PDGF-CC was antagonized by both PDGF receptor alpha and PDGF receptor beta neutralizing antibodies; in contrast, PDGF-BB was only inhibited by PDGF receptor beta blocking antibody. PDGF receptor alpha and PDGF receptor beta inhibition prevented PDGF-CC-induced ERK phosphorylation. PDGF-CC induces TF expression via activation of alpha/beta receptor heterodimers and an ERK-dependent signal transduction pathway.
组织因子（TF）是凝血级联反应的主要触发因子，并参与动脉血栓形成。血小板衍生生长因子 CC（PDGF-CC）是血小板激活时释放的 PDGF 家族的新成员。本研究评估了 PDGF-CC 对人细胞 TF 表达的影响。PDGF-CC 浓度依赖性地诱导 THP-1 细胞 TF 表达增加 2.5 倍，人外周血单核细胞增加 2.0 倍，血管平滑肌细胞增加 1.4 倍，微血管内皮细胞增加 2.6 倍，但不影响主动脉内皮细胞的 TF 表达。PDGF-BB 也观察到类似的模式。相比之下，PDGF-AA 不会改变 THP-1 细胞中的 TF 表达。PDGF-BB 和 PDGF-CC 刺激 THP-1 细胞后诱导 TF 全细胞活性。实时聚合酶链反应显示 PDGF-CC 诱导 TF mRNA。PDGF-CC 短暂激活 p42/44 MAP 激酶 [细胞外信号调节激酶（ERK）]，而 MAP 激酶 c-Jun NH2-末端激酶（JNK）和 p38 的磷酸化不受影响。PD98059 是 ERK 磷酸化的特异性抑制剂，但 p38 抑制剂 SB203580 或 JNK 抑制剂 SP600125 不能阻止 PDGF-CC 浓度依赖性诱导的 TF 表达。PDGF-CC 的作用被 PDGF 受体 alpha 和 PDGF 受体 beta 中和抗体拮抗；相比之下，PDGF-BB 仅被 PDGF 受体 beta 阻断抗体抑制。PDGF 受体 alpha 和 PDGF 受体 beta 抑制阻止了 PDGF-CC 诱导的 ERK 磷酸化。PDGF-CC 通过激活 alpha/beta 受体异二聚体和 ERK 依赖的信号转导途径诱导 TF 表达。
