Ets-1 mediates platelet-derived growth factor-BB-induced thrombomodulin expression in human vascular smooth muscle cells

被引:27
作者
Lo, I. -Chung [1 ,2 ]
Lin, Tsun-Mei [3 ,4 ]
Chou, Ling-Hui [2 ]
Liu, Shu-Lin [4 ,5 ]
Wu, Li-Wha [1 ,4 ,6 ]
Shi, Guey-Yueh [1 ,4 ,5 ]
Wu, Hua-Lin [1 ,4 ,5 ]
Jiang, Meei Jyh [1 ,2 ,4 ]
机构
[1] Natl Cheng Kung Univ, Coll Med, Inst Basic Med Sci, Tainan 70101, Taiwan
[2] Natl Cheng Kung Univ, Coll Med, Dept Cell Biol & Anat, Tainan 70101, Taiwan
[3] Natl Cheng Kung Univ, Coll Med, Dept Med Lab Sci & Biotechnol, Tainan 70101, Taiwan
[4] Natl Cheng Kung Univ, Coll Med, Cardiovasc Res Ctr, Tainan 70101, Taiwan
[5] Natl Cheng Kung Univ, Coll Med, Dept Biochem & Mol Biol, Tainan 70101, Taiwan
[6] Natl Cheng Kung Univ, Coll Med, Inst Mol Med, Tainan 70101, Taiwan
关键词
Thrombomodulin; Platelet-derived growth factor-BB; Vascular smooth muscle; Ets-1; Phosphatidylinositol; 3-kinase; FACTOR-KAPPA-B; NEOINTIMA FORMATION; THROMBIN RECEPTOR; PROTEIN; ATHEROSCLEROSIS; TRANSCRIPTION; DISEASE; INFLAMMATION; ACTIVATION; INDUCTION;
D O I
10.1093/cvr/cvn351
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Thrombomodulin (TM), a potent anticoagulant, is not detected in quiescent vascular smooth muscle cells (VSMCs). In diseased vessels, VSMC expresses TM, but the mechanisms are unclear. This study examined molecular mechanisms for TM expression in VSMCs. Platelet-derived growth factor-BB (PDGF-BB) induced TM expression in cultured human aortic VSMCs. PDGF-induced TM is functional in activating protein C. TM induction was eliminated by inhibitors of Src kinase, phosphatidylinositol 3-kinase (PI3-kinase), and mammalian target of rapamycin (mTOR) and by expressing dominant-negative Akt while expressing active Akt-stimulated TM expression. PDGF-BB activated the TM promoter, and the deletion of a sequence segment -394/-255 drastically reduced TM promoter activity. Transcription factor E26 transformation-specific sequence-1 (Ets-1) was upregulated by PDGF-BB in a PI3-kinase- and mTOR-dependent manner. RNA interference of Ets-1 inhibited PDGF induction of TM, and overexpressing Ets-1 increased TM expression. Chromatin immunoprecipitation and electrophoretic mobility shift assay detected increased Ets-1 binding to the TM promoter after PDGF treatment. Following carotid artery ligation of C57/BL6 mice, PDGF-BB and TM were co-expressed in the media and neointima. In VSMCs, PDGF-BB stimulates TM expression that is mainly mediated by Ets-1 via the Src kinase/PI3-kinase/Akt/mTOR signalling pathway. Furthermore, PDGF-BB may regulate TM expression in VSMCs during vascular remodelling.
引用
收藏
页码:771 / 779
页数:9
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