PMID- 11440977
OWN - NLM
STAT- MEDLINE
DCOM- 20010823
LR  - 20190706
IS  - 1524-4571 (Electronic)
IS  - 0009-7330 (Linking)
VI  - 89
IP  - 1
DP  - 2001 Jul 6
TI  - Thrombin activates the hypoxia-inducible factor-1 signaling pathway in vascular 
      smooth muscle cells: Role of the p22(phox)-containing NADPH oxidase.
PG  - 47-54
AB  - The heterodimeric transcription factor hypoxia-inducible factor-1 (HIF-1) is 
      activated under hypoxic conditions, resulting in the upregulation of its target 
      genes plasminogen activator inhibitor-1 (PAI-1) and vascular endothelial growth 
      factor (VEGF). PAI-1 and VEGF are also induced in response to vascular injury, 
      which is characterized by the activation of platelets and the coagulation cascade 
      as well as the generation of reactive oxygen species (ROS). However, it is not 
      known whether HIF-1 is also stimulated by thrombotic factors. We investigated the 
      role of thrombin, platelet-associated growth factors, and ROS derived from the 
      p22(phox)-containing NADPH oxidase in the activation of HIF-1 and the induction 
      of its target genes PAI-1 and VEGF in human vascular smooth muscle cells (VSMCs). 
      Thrombin, platelet-derived growth factor-AB (PDGF-AB), and transforming growth 
      factor-beta(1) (TGF-beta(1)) upregulated HIF-1alpha protein in cultured and 
      native VSMCs. This response was accompanied by nuclear accumulation of HIF-1alpha 
      as well as by increased HIF-1 DNA-binding and reporter gene activity. The 
      thrombin-induced expression of HIF-1alpha, PAI-1, and VEGF was attenuated by 
      antioxidant treatment as well as by transfection of p22(phox) antisense 
      oligonucleotides. Inhibition of p38 mitogen-activated protein kinase and 
      phosphatidylinositol-3-kinase significantly decreased thrombin-induced 
      HIF-1alpha, PAI-1, and VEGF expression. These findings demonstrate that the HIF-1 
      signaling pathway can be stimulated by thrombin and platelet-associated growth 
      factors and that a redox-sensitive cascade activated by ROS derived from the 
      p22(phox)-containing NADPH oxidase is crucially involved in this response.
FAU - Gorlach, A
AU  - Gorlach A
AD  - Institut fur Kardiovaskulare Physiologie, Klinikum der J.W. Goethe-Universitat, 
      Frankfurt/M, Germany. A.Goerlach@em.uni-frankfurt.de
FAU - Diebold, I
AU  - Diebold I
FAU - Schini-Kerth, V B
AU  - Schini-Kerth VB
FAU - Berchner-Pfannschmidt, U
AU  - Berchner-Pfannschmidt U
FAU - Roth, U
AU  - Roth U
FAU - Brandes, R P
AU  - Brandes RP
FAU - Kietzmann, T
AU  - Kietzmann T
FAU - Busse, R
AU  - Busse R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Circ Res
JT  - Circulation research
JID - 0047103
RN  - 0 (Antioxidants)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Endothelial Growth Factors)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Lymphokines)
RN  - 0 (Membrane Transport Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Phosphoproteins)
RN  - 0 (Plasminogen Activator Inhibitor 1)
RN  - 0 (Platelet-Derived Growth Factor)
RN  - 0 (RNA, Messenger)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Transcription Factors)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - 0 (platelet-derived growth factor AB)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 1.6.3.1 (CYBA protein, human)
RN  - EC 1.6.99.1 (NADPH Dehydrogenase)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 3.4.21.5 (Thrombin)
SB  - IM
MH  - Antioxidants/pharmacology
MH  - Cells, Cultured
MH  - DNA-Binding Proteins/*metabolism/physiology
MH  - Endothelial Growth Factors/biosynthesis/genetics
MH  - Humans
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Lymphokines/biosynthesis/genetics
MH  - *Membrane Transport Proteins
MH  - Mitogen-Activated Protein Kinases/physiology
MH  - Muscle, Smooth, Vascular/drug effects/enzymology/*metabolism
MH  - NADPH Dehydrogenase/*physiology
MH  - NADPH Oxidases/*physiology
MH  - Nuclear Proteins/*metabolism/physiology
MH  - Phosphatidylinositol 3-Kinases/physiology
MH  - Phosphoproteins/*physiology
MH  - Plasminogen Activator Inhibitor 1/biosynthesis/genetics
MH  - Platelet-Derived Growth Factor/pharmacology
MH  - RNA, Messenger/biosynthesis
MH  - Reactive Oxygen Species/physiology
MH  - *Signal Transduction
MH  - Thrombin/*pharmacology
MH  - *Transcription Factors
MH  - Transcriptional Activation
MH  - Vascular Endothelial Growth Factor A
MH  - Vascular Endothelial Growth Factors
MH  - p38 Mitogen-Activated Protein Kinases
EDAT- 2001/07/07 10:00
MHDA- 2001/08/24 10:01
CRDT- 2001/07/07 10:00
PHST- 2001/07/07 10:00 [pubmed]
PHST- 2001/08/24 10:01 [medline]
PHST- 2001/07/07 10:00 [entrez]
AID - 10.1161/hh1301.092678 [doi]
PST - ppublish
SO  - Circ Res. 2001 Jul 6;89(1):47-54. doi: 10.1161/hh1301.092678.