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Blood, 15 July 2008, Vol. 112, No. 2, pp. 330-339. Prepublished online as a Blood First Edition Paper on May 1, 2008; DOI 10.1182/blood-2007-09-112870. This Article Full Text Full Text (PDF) Supplemental Results and Figures All Versions of this Article: blood-2007-09-112870v1 112/2/330    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Oskolkova, O. V. Articles by Bochkov, V. N. Search for Related Content PubMed PubMed Citation Articles by Oskolkova, O. V. Articles by Bochkov, V. N. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY ATF4-dependent transcription is a key mechanism in VEGF up-regulation by oxidized phospholipids: critical role of oxidized sn-2 residues in activation of unfolded protein response Olga V. Oskolkova1,*, Taras Afonyushkin1,*, Alexander Leitner2, Elena von Schlieffen1, Peter S. Gargalovic3, Aldons J. Lusis3, Bernd R. Binder1, and Valery N. Bochkov1 1 Department of Vascular Biology and Thrombosis Research, Center for Biomolecular Medicine and Pharmacology, Medical University of Vienna, Vienna, Austria; 2 Department of Analytical Chemistry and Food Chemistry, University of Vienna, Vienna, Austria; and 3 Department of Medicine, Division of Cardiology, University of California, Los Angeles We have shown previously that oxidized phospholipids (OxPLs), known to accumulate in atherosclerotic vessels, stimulate angiogenesis via induction of autocrine mediators, such as vascular endothelial growth factor (VEGF). We now address the pathways mediating up-regulation of VEGF in human endothelial cells treated with OxPLs. Analysis of structure-function relationship using individual species of OxPLs demonstrated a close relation between induction of VEGF and activation of the unfolded protein response (UPR). Inducers of UPR up-regulated VEGF, whereas inhibition of UPR by chemical chaperones or knock-down of cochaperone HTJ-1 inhibited elevation of VEGF mRNA induced by OxPLs. OxPLs induced protein expression of activating transcription factor-4 (ATF4), an important effector of UPR. Expression levels of VEGF in OxPL-treated cells strongly correlated with induction of the ATF4 target genes ATF3 and TRB3. Knocking down ATF4 was paralleled by loss of VEGF induction by OxPLs. Chromatin immunoprecipitation demonstrated that OxPLs stimulated binding of ATF4 to a regulatory site in the VEGFA gene. Taken together, these data characterize UPR and more specifically its ATF4 branch as an important mechanism mediating up-regulation of VEGF by OxPLs, and allow hypothesizing that the UPR cascade might play a role in pathologic angiogenesis in atherosclerotic plaques. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. F. Abcouwer and C. N. Roybal Regulation of Vascular Endothelial Growth Factor A by Activating Transcription Factor 4 Circ. Res., October 24, 2008; 103(9): e118 - e118. [Full Text] [PDF] L. M. Khachigian, A. Bobik, P. Kanellakis, and K. Malabanan Response to Abcouwer and Roybal Circ. Res., October 24, 2008; 103(9): e119 - e119. [Full Text] [PDF]

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