A novel role for activating transcription factor-2 in 15(S)-hydroxyeicosatetraenoic acid-induced angiogenesis.

Autor:	Zhao T; T. Zhao and D. Wang contributed equally to this work; Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163., Wang D; T. Zhao and D. Wang contributed equally to this work; Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163., Cheranov SY; Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163., Karpurapu M; Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163., Chava KR; Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163., Kundumani-Sridharan V; Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163., Johnson DA; Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163., Penn JS; Vanderbilt Eye Institute, Vanderbilt University School of Medicine, Nashville, TN 37232., Rao GN; Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163. Electronic address: grao@physio1.utmem.edu.
Jazyk:	angličtina
Zdroj:	Journal of lipid research [J Lipid Res] 2009 Mar; Vol. 50 (3), pp. 521-533. Date of Electronic Publication: 2008 Oct 10.
DOI:	10.1194/jlr.M800388-JLR200
Abstrakt:	To investigate the mechanisms underlying 15(S)-HETE-induced angiogenesis, we have studied the role of the small GTPase, Rac1. We find that 15(S)-HETE activated Rac1 in human retinal microvascular endothelial cells (HRMVEC) in a time-dependent manner. Blockade of Rac1 by adenovirus-mediated expression of its dominant negative mutant suppressed HRMVEC migration as well as tube formation and Matrigel plug angiogenesis. 15(S)-HETE stimulated Src in HRMVEC in a time-dependent manner and blockade of its activation inhibited 15(S)-HETE-induced Rac1 stimulation in HRMVEC and the migration and tube formation of these cells as well as Matrigel plug angiogenesis. 15(S)-HETE stimulated JNK1 in Src-Rac1-dependent manner in HRMVEC and adenovirus-mediated expression of its dominant negative mutant suppressed the migration and tube formation of these cells and Matrigel plug angiogenesis. 15(S)-HETE activated ATF-2 in HRMVEC in Src-Rac1-JNK1-dependent manner and interference with its activation via adenovirus-mediated expression of its dominant negative mutant abrogated migration and tube formation of HRMVEC and Matrigel plug angiogenesis. In addition, 15(S)-HETE-induced MEK1 stimulation was found to be dependent on Src-Rac1 activation. Blockade of MEK1 activation inhibited 15(S)-HETE-induced JNK1 activity and ATF-2 phosphorylation. Together, these findings show that 15(S)-HETE activates ATF-2 via the Src-Rac1-MEK1-JNK1 signaling axis in HRMVEC leading to their angiogenic differentiation.
Databáze:	MEDLINE
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