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

Autor: Li Wha Wu, Hua Lin Wu, Ling Hui Chou, I. Chung Lo, Guey Yueh Shi, Shu-Lin Liu, Tsun-Mei Lin, Meei Jyh Jiang
Rok vydání: 2008
Předmět:
Male
Time Factors
Platelet-derived growth factor
Vascular smooth muscle
Physiology
Thrombomodulin
Myocytes
Smooth Muscle
Becaplermin
Transfection
Muscle
Smooth
Vascular
Proto-Oncogene Protein c-ets-1
Mice
Phosphatidylinositol 3-Kinases
chemistry.chemical_compound
Physiology (medical)
Animals
Humans
RNA
Messenger
Extracellular Signal-Regulated MAP Kinases
Promoter Regions
Genetic
Protein kinase B
Cells
Cultured
PI3K/AKT/mTOR pathway
Platelet-Derived Growth Factor
biology
TOR Serine-Threonine Kinases
Proto-Oncogene Proteins c-sis
Recombinant Proteins
Up-Regulation
Cell biology
Mice
Inbred C57BL
Disease Models
Animal
src-Family Kinases
chemistry
cardiovascular system
Cancer research
biology.protein
RNA Interference
Signal transduction
Carotid Artery Injuries
Cardiology and Cardiovascular Medicine
Protein Kinases
Proto-Oncogene Proteins c-akt
Platelet-derived growth factor receptor
Signal Transduction
Proto-oncogene tyrosine-protein kinase Src
Zdroj: Cardiovascular Research. 81:771-779
ISSN: 1755-3245
0008-6363
DOI: 10.1093/cvr/cvn351
Popis: Aims 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. Methods and results 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. Conclusion 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.
Databáze: OpenAIRE
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