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

Tieqiang Zhao; Dong Wang; Sergey Y. Cheranov; Manjula Karpurapu; Koteswara R. Chava; Venkatesh Kundumani-Sridharan; Dianna A. Johnson; John S. Penn; Gadiparthi N. Rao

Journal of Lipid Research (Mar 2009)

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

Tieqiang Zhao,
Dong Wang,
Sergey Y. Cheranov,
Manjula Karpurapu,
Koteswara R. Chava,
Venkatesh Kundumani-Sridharan,
Dianna A. Johnson,
John S. Penn,
Gadiparthi N. Rao

Affiliations

Tieqiang Zhao: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163; Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163; Vanderbilt Eye Institute, Vanderbilt University School of Medicine, Nashville, TN 37232; T. Zhao and D. Wang contributed equally to this work
Dong Wang: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163; Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163; Vanderbilt Eye Institute, Vanderbilt University School of Medicine, Nashville, TN 37232; T. Zhao and D. Wang contributed equally to this work
Sergey Y. Cheranov: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163; Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163; Vanderbilt Eye Institute, Vanderbilt University School of Medicine, Nashville, TN 37232; T. Zhao and D. Wang contributed equally to this work
Manjula Karpurapu: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163; Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163; Vanderbilt Eye Institute, Vanderbilt University School of Medicine, Nashville, TN 37232; T. Zhao and D. Wang contributed equally to this work
Koteswara R. Chava: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163; Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163; Vanderbilt Eye Institute, Vanderbilt University School of Medicine, Nashville, TN 37232; T. Zhao and D. Wang contributed equally to this work
Venkatesh Kundumani-Sridharan: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163; Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163; Vanderbilt Eye Institute, Vanderbilt University School of Medicine, Nashville, TN 37232; T. Zhao and D. Wang contributed equally to this work
Dianna A. Johnson: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163; Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163; Vanderbilt Eye Institute, Vanderbilt University School of Medicine, Nashville, TN 37232; T. Zhao and D. Wang contributed equally to this work
John S. Penn: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163; Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163; Vanderbilt Eye Institute, Vanderbilt University School of Medicine, Nashville, TN 37232; T. Zhao and D. Wang contributed equally to this work
Gadiparthi N. Rao: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163; Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163; Vanderbilt Eye Institute, Vanderbilt University School of Medicine, Nashville, TN 37232; T. Zhao and D. Wang contributed equally to this work

Journal volume & issue: Vol. 50, no. 3
pp. 521 – 533

Abstract

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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.

Published in Journal of Lipid Research

ISSN: 0022-2275 (Print); 1539-7262 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Chemistry: Organic chemistry: Biochemistry
Website: https://www.journals.elsevier.com/journal-of-lipid-research

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