PMID- 21536676
OWN - NLM
STAT- MEDLINE
DCOM- 20110830
LR  - 20211020
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 286
IP  - 25
DP  - 2011 Jun 24
TI  - 15-Lipoxygenase-1-enhanced Src-Janus kinase 2-signal transducer and activator of 
      transcription 3 stimulation and monocyte chemoattractant protein-1 expression 
      require redox-sensitive activation of epidermal growth factor receptor in 
      vascular wall remodeling.
PG  - 22478-88
LID - 10.1074/jbc.M111.225060 [doi]
AB  - To understand the mechanisms by which 15(S)-hydroxyeicosatetraenoic acid 
      (15(S)-HETE) activates signal transducer and activator of transcription 3 
      (STAT3), we studied the role of epidermal growth factor receptor (EGFR). 
      15(S)-HETE stimulated tyrosine phosphorylation of EGFR in a time-dependent manner 
      in vascular smooth muscle cells (VSMCs). Interference with EGFR activation 
      blocked 15(S)-HETE-induced Src and STAT3 tyrosine phosphorylation, monocyte 
      chemoattractant protein-1 (MCP-1) expression and VSMC migration. 15(S)-HETE also 
      induced tyrosine phosphorylation of Janus kinase 2 (Jak2) in VSMCs, and its 
      inhibition substantially reduced STAT3 phosphorylation, MCP-1 expression, and 
      VSMC migration. In addition, Src formed a complex with EGFR and Jak2, and its 
      inhibition completely blocked Jak2 and STAT3 phosphorylation, MCP-1 expression, 
      and VSMC migration. 15(S)-HETE induced the production of H(2)O(2) via an NADPH 
      oxidase-dependent manner and its scavengers, N-acetyl cysteine (NAC) and catalase 
      suppressed 15(S)-HETE-stimulated EGFR, Src, Jak2, and STAT3 phosphorylation and 
      MCP-1 expression. Balloon injury (BI) induced EGFR, Src, Jak2, and STAT3 
      phosphorylation, and inhibition of these signaling molecules attenuated 
      BI-induced MCP-1 expression and smooth muscle cell migration from the medial to 
      the luminal surface resulting in reduced neointima formation. In addition, 
      inhibition of EGFR blocked BI-induced Src, Jak2, and STAT3 phosphorylation. 
      Similarly, interference with Src activation suppressed BI-induced Jak2 and STAT3 
      phosphorylation. Furthermore, adenovirus-mediated expression of dnJak2 also 
      blocked BI-induced STAT3 phosphorylation. Consistent with the effects of 
      15(S)-HETE on the activation of EGFR-Src-Jak2-STAT3 signaling in VSMCs in vitro, 
      adenovirus-mediated expression of 15-lipoxygenase 1 (15-Lox1) enhanced BI-induced 
      EGFR, Src, Jak2, and STAT3 phosphorylation leading to enhanced MCP-1 expression 
      in vivo. Blockade of Src or Jak2 suppressed BI-induced 15-Lox1-enhanced STAT3 
      phosphorylation, MCP-1 expression, and neointima formation. In addition, whereas 
      dominant negative Src blocked BI-induced 15-Lox1-enhanced Jak2 phosphorylation, 
      dnJak2 had no effect on Src phosphorylation. Together, these observations 
      demonstrate for the first time that the 15-Lox1-15(S)-HETE axis activates EGFR 
      via redox-sensitive manner, which in turn mediates Src-Jak2-STAT3-dependent MCP-1 
      expression leading to vascular wall remodeling.
FAU - Singh, Nikhlesh K
AU  - Singh NK
AD  - Department of Physiology, The University of Tennessee Health Science Center, 
      Memphis, Tennessee 38163, USA.
FAU - Wang, Dong
AU  - Wang D
FAU - Kundumani-Sridharan, Venkatesh
AU  - Kundumani-Sridharan V
FAU - Van Quyen, Dong
AU  - Van Quyen D
FAU - Niu, Jixiao
AU  - Niu J
FAU - Rao, Gadiparthi N
AU  - Rao GN
LA  - eng
GR  - R01 HL064165/HL/NHLBI NIH HHS/United States
GR  - HL064165/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20110502
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Chemokine CCL2)
RN  - 0 (Hydroxyeicosatetraenoic Acids)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (STAT3 Transcription Factor)
RN  - 42HK56048U (Tyrosine)
RN  - 73945-47-8 (15-hydroxy-5,8,11,13-eicosatetraenoic acid)
RN  - EC 1.13.11.33 (Arachidonate 15-Lipoxygenase)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.2 (Janus Kinase 2)
RN  - EC 2.7.10.2 (Proto-Oncogene Proteins pp60(c-src))
SB  - IM
MH  - Adenoviridae/genetics
MH  - Animals
MH  - Arachidonate 15-Lipoxygenase/*metabolism
MH  - Blood Vessels/*drug effects/metabolism/physiology
MH  - Carotid Artery Injuries/genetics/metabolism/pathology/physiopathology
MH  - Cell Movement/drug effects
MH  - Chemokine CCL2/genetics/*metabolism
MH  - ErbB Receptors/chemistry/*metabolism
MH  - Gene Expression Regulation/drug effects
MH  - HEK293 Cells
MH  - Humans
MH  - Hydroxyeicosatetraenoic Acids/pharmacology
MH  - Janus Kinase 2/chemistry/genetics/*metabolism
MH  - Muscle, Smooth, Vascular/cytology/drug effects/metabolism
MH  - Oxidation-Reduction/drug effects
MH  - Phosphorylation/drug effects
MH  - Proto-Oncogene Proteins pp60(c-src)/*metabolism
MH  - Rats
MH  - Reactive Oxygen Species/metabolism
MH  - STAT3 Transcription Factor/genetics/*metabolism
MH  - Signal Transduction/drug effects
MH  - Tyrosine/metabolism
PMC - PMC3121393
EDAT- 2011/05/04 06:00
MHDA- 2011/08/31 06:00
PMCR- 2012/06/24
CRDT- 2011/05/04 06:00
PHST- 2011/05/04 06:00 [entrez]
PHST- 2011/05/04 06:00 [pubmed]
PHST- 2011/08/31 06:00 [medline]
PHST- 2012/06/24 00:00 [pmc-release]
AID - S0021-9258(19)48957-6 [pii]
AID - M111.225060 [pii]
AID - 10.1074/jbc.M111.225060 [doi]
PST - ppublish
SO  - J Biol Chem. 2011 Jun 24;286(25):22478-88. doi: 10.1074/jbc.M111.225060. Epub 
      2011 May 2.