Document Detail

AP-1 (Fra-1/c-Jun)-mediated induction of expression of matrix metalloproteinase-2 is required for 15S-hydroxyeicosatetraenoic acid-induced angiogenesis.
MedLine Citation:
PMID:  20353950     Owner:  NLM     Status:  MEDLINE    
To understand the involvement of matrix metalloproteinases (MMPs) in 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE)-induced angiogenesis, we have studied the role of MMP-2. 15(S)-HETE induced MMP-2 expression and activity in a time-dependent manner in human dermal microvascular endothelial cells (HDMVECs). Inhibition of MMP-2 activity or depletion of its levels attenuated 15(S)-HETE-induced HDMVEC migration, tube formation, and Matrigel plug angiogenesis. 15(S)-HETE also induced Fra-1 and c-Jun expression in a Rac1-MEK1-JNK1-dependent manner. In addition, 15(S)-HETE-induced MMP-2 expression and activity were mediated by Rac1-MEK1-JNK1-dependent activation of AP-1 (Fra-1/c-Jun). Cloning and site-directed mutagenesis of MMP-2 promoter revealed that AP-1 site proximal to the transcriptional start site is required for 15(S)-HETE-induced MMP-2 expression, and Fra-1 and c-Jun are the essential components of AP-1 that bind to MMP-2 promoter in response to 15(S)-HETE. Hind limb ischemia led to an increase in MEK1 and JNK1 activation and Fra-1, c-Jun, and MMP-2 expression resulting in enhanced neovascularization and recovery of blood perfusion in wild-type mice as compared with 12/15-Lox(-/-) mice. Together, these results provide the first direct evidence for a role of 12/15-Lox-12/15(S)-HETE axis in the regulation of ischemia-induced angiogenesis.
Nikhlesh K Singh; Dong Van Quyen; Venkatesh Kundumani-Sridharan; Peter C Brooks; Gadiparthi N Rao
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-03-29
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-24     Completed Date:  2010-06-17     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  16830-43     Citation Subset:  IM    
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MeSH Terms
Base Sequence
Cell Movement
Gene Expression Regulation, Enzymologic*
Hydroxyeicosatetraenoic Acids / metabolism*
Matrix Metalloproteinase 2 / metabolism*
Mice, Inbred C57BL
Mice, Transgenic
Molecular Sequence Data
Neovascularization, Pathologic*
Promoter Regions, Genetic
Proto-Oncogene Proteins c-fos / metabolism
Transcription Factor AP-1 / physiology*
Grant Support
Reg. No./Substance:
0/Hydroxyeicosatetraenoic Acids; 0/Proto-Oncogene Proteins c-fos; 0/Transcription Factor AP-1; 0/fos-related antigen 1; 73945-47-8/15-hydroxy-5,8,11,13-eicosatetraenoic acid; EC Metalloproteinase 2

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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