PMID- 19132225
OWN - NLM
STAT- MEDLINE
DCOM- 20090212
LR  - 20090109
IS  - 0340-6245 (Print)
IS  - 0340-6245 (Linking)
VI  - 100
IP  - 6
DP  - 2008 Dec
TI  - Rac-1 promotes pulmonary artery smooth muscle cell proliferation by upregulation 
      of plasminogen activator inhibitor-1: role of NFkappaB-dependent 
      hypoxia-inducible factor-1alpha transcription.
PG  - 1021-8
AB  - Pulmonary vascular remodeling is commonly associated with pulmonary hypertension 
      and is characterized by media thickening and disordered cellular proliferation, 
      often accompanied by fibrin deposition and thrombosis in situ. However, the 
      signaling pathways linking these different processes are not well understood. 
      Since the GTPase Rac-1 has been suggested to act as a signaling relay in various 
      cell types we investigated whether Rac-1 could be the link between thrombin 
      signaling, plasminogen activator inhibitor-1 (PAI-1), which inhibits fibrinolysis 
      and promotes fibrin deposition, and proliferation of pulmonary artery smooth 
      muscle cells (PASMC). Exposure to thrombin enhanced the levels of Rac-1 protein 
      and increased PAI-1 mRNA and protein expression in dependence of the thrombin 
      receptor PAR-1. Expression of dominant-negative Rac-1 (RacT17N) prevented 
      thrombin-induced PAI-1 expression whereas constitutively active RacG12V enhanced 
      PAI-1 levels. In the presence of RacT17N thrombin-induced PAI-1 promoter activity 
      was abrogated whereas RacG12V increased PAI-1 promoter activity, and this 
      response was essentially dependent on the transcription factor hypoxia-inducible 
      factor-1 (HIF-1). Subsequently, RacG12V not only increased HIF transcriptional 
      activity but also HIF-1alpha protein and mRNA levels, whereas RacT17N prevented 
      these responses elicited by thrombin. In line, RacG12V enhanced HIF-1alpha 
      promoter activity, and this response was dependent on nuclear factor-kappaB 
      (NFkappaB) binding to the HIF-1alpha promoter. Finally, upregulation of PAI-1 by 
      Rac-1 and HIF-1 was essential for thrombin-stimulated proliferation of PASMC. 
      These findings indicate that Rac-1 is an important mediator of thrombin signaling 
      and may contribute to pulmonary vascular remodeling via HIF-1-dependent 
      upregulation of PAI-1 leading to enhanced proliferation of PASMC.
FAU - Diebold, Isabel
AU  - Diebold I
AD  - Experimentelle Kinderkardiologie, Deutsches Herzzentrum Munchen, an der 
      Technischen Universitat Munchen, Lazarettstr. 36, D-80636 Munchen, Germany.
FAU - Djordjevic, Talija
AU  - Djordjevic T
FAU - Hess, John
AU  - Hess J
FAU - Gorlach, Agnes
AU  - Gorlach A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Germany
TA  - Thromb Haemost
JT  - Thrombosis and haemostasis
JID - 7608063
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (NF-kappa B)
RN  - 0 (Plasminogen Activator Inhibitor 1)
RN  - 0 (RAC1 protein, human)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptor, PAR-1)
RN  - 0 (SERPINE1 protein, human)
RN  - EC 3.4.21.5 (Thrombin)
RN  - EC 3.6.5.2 (rac1 GTP-Binding Protein)
SB  - IM
MH  - Animals
MH  - *Cell Proliferation
MH  - Cells, Cultured
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
MH  - Muscle, Smooth, Vascular/*enzymology
MH  - Myocytes, Smooth Muscle/*enzymology
MH  - NF-kappa B/*metabolism
MH  - Plasminogen Activator Inhibitor 1/genetics/*metabolism
MH  - Pulmonary Artery/enzymology
MH  - RNA Interference
MH  - RNA, Messenger/metabolism
MH  - RNA, Small Interfering/metabolism
MH  - Rats
MH  - Receptor, PAR-1/metabolism
MH  - Signal Transduction
MH  - Thrombin/metabolism
MH  - Time Factors
MH  - *Transcription, Genetic
MH  - Transfection
MH  - Up-Regulation
MH  - rac1 GTP-Binding Protein/*metabolism
EDAT- 2009/01/10 09:00
MHDA- 2009/02/13 09:00
CRDT- 2009/01/10 09:00
PHST- 2009/01/10 09:00 [entrez]
PHST- 2009/01/10 09:00 [pubmed]
PHST- 2009/02/13 09:00 [medline]
AID - 08121021 [pii]
PST - ppublish
SO  - Thromb Haemost. 2008 Dec;100(6):1021-8.