AP-1 (Fra-1/c-Jun)-mediated Induction of Expression of Matrix Metalloproteinase-2 Is Required for 15(S)-Hydroxyeicosatetraenoic Acid-induced Angiogenesis

• Published in: The Journal of biological chemistry Vol. 285; no. 22; pp. 16830 - 16843
• Main Authors: Singh, Nikhlesh K., Quyen, Dong Van, Kundumani-Sridharan, Venkatesh, Brooks, Peter C., Rao, Gadiparthi N.
• Format: Journal Article
• Language: English
• Published: 9650 Rockville Pike, Bethesda, MD 20814, U.S.A Elsevier Inc 28.05.2010; American Society for Biochemistry and Molecular Biology
• Subjects: Angiogenesis; AP-1 Transcription Factor; Cell Migration; Ischemia; Lipoxygenase Pathway; Matrix Metalloproteinase; Molecular Bases of Disease; Signal Transduction; Cell Migration; Angiogenesis; Ischemia; AP-1 Transcription Factor; Lipoxygenase Pathway; Matrix Metalloproteinase
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.106187

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.