PMID- 19091791
OWN - NLM
STAT- MEDLINE
DCOM- 20090611
LR  - 20211203
IS  - 1755-3245 (Electronic)
IS  - 0008-6363 (Linking)
VI  - 81
IP  - 4
DP  - 2009 Mar 1
TI  - Ets-1 mediates platelet-derived growth factor-BB-induced thrombomodulin 
      expression in human vascular smooth muscle cells.
PG  - 771-9
LID - 10.1093/cvr/cvn351 [doi]
AB  - 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.
FAU - Lo, I-Chung
AU  - Lo IC
AD  - Institute of Basic Medical Sciences, National Cheng Kung University College of 
      Medicine, Tainan, Taiwan, Republic of China.
FAU - Lin, Tsun-Mei
AU  - Lin TM
FAU - Chou, Ling-Hui
AU  - Chou LH
FAU - Liu, Shu-Lin
AU  - Liu SL
FAU - Wu, Li-Wha
AU  - Wu LW
FAU - Shi, Guey-Yueh
AU  - Shi GY
FAU - Wu, Hua-Lin
AU  - Wu HL
FAU - Jiang, Meei Jyh
AU  - Jiang MJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20081217
PL  - England
TA  - Cardiovasc Res
JT  - Cardiovascular research
JID - 0077427
RN  - 0 (ETS1 protein, human)
RN  - 0 (Platelet-Derived Growth Factor)
RN  - 0 (Proto-Oncogene Protein c-ets-1)
RN  - 0 (Proto-Oncogene Proteins c-sis)
RN  - 0 (RNA, Messenger)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Thrombomodulin)
RN  - 1B56C968OA (Becaplermin)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.10.2 (src-Family Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - Animals
MH  - Becaplermin
MH  - Carotid Artery Injuries/metabolism
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Muscle, Smooth, Vascular/*metabolism
MH  - Myocytes, Smooth Muscle/*metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Platelet-Derived Growth Factor/*metabolism
MH  - Promoter Regions, Genetic
MH  - Protein Kinases/metabolism
MH  - Proto-Oncogene Protein c-ets-1/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Proto-Oncogene Proteins c-sis
MH  - RNA Interference
MH  - RNA, Messenger/metabolism
MH  - Recombinant Proteins/metabolism
MH  - *Signal Transduction
MH  - TOR Serine-Threonine Kinases
MH  - Thrombomodulin/genetics/*metabolism
MH  - Time Factors
MH  - Transfection
MH  - Up-Regulation
MH  - src-Family Kinases/metabolism
EDAT- 2008/12/19 09:00
MHDA- 2009/06/12 09:00
CRDT- 2008/12/19 09:00
PHST- 2008/12/19 09:00 [entrez]
PHST- 2008/12/19 09:00 [pubmed]
PHST- 2009/06/12 09:00 [medline]
AID - cvn351 [pii]
AID - 10.1093/cvr/cvn351 [doi]
PST - ppublish
SO  - Cardiovasc Res. 2009 Mar 1;81(4):771-9. doi: 10.1093/cvr/cvn351. Epub 2008 Dec 
      17.