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J. Biol. Chem., Vol. 282, Issue 47, 34468-34478, November 23, 2007

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The Confluence-dependent Interaction of Cytosolic Phospholipase A₂- with Annexin A1 Regulates Endothelial Cell Prostaglandin E₂ Generation^*

From the Faculty of Biological Sciences, Institute of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom

The regulated generation of prostaglandins from endothelial cells is critical to vascular function. Here we identify a novel mechanism for the regulation of endothelial cell prostaglandin generation. Cytosolic phospholipase A₂- (cPLA₂) cleaves phospholipids in a Ca²⁺-dependent manner to yield free arachidonic acid and lysophospholipid. Arachidonic acid is then converted into prostaglandins by the action of cyclooxygenase enzymes and downstream synthases. By previously undefined mechanisms, nonconfluent endothelial cells generate greater levels of prostaglandins than confluent cells. Here we demonstrate that Ca²⁺-independent association of cPLA₂ with the Golgi apparatus of confluent endothelial cells correlates with decreased prostaglandin synthesis. Golgi association blocks arachidonic acid release and prevents functional coupling between cPLA₂ and COX-mediated prostaglandin synthesis. When inactivated at the Golgi apparatus of confluent endothelial cells, cPLA₂ is associated with the phospholipid-binding protein annexin A1. Furthermore, the siRNA-mediated knockdown of endogenous annexin A1 significantly reverses the inhibitory effect of confluence on endothelial cell prostaglandin generation. Thus the confluence-dependent interaction of cPLA₂ and annexin A1 at the Golgi acts as a novel molecular switch controlling cPLA₂ activity and endothelial cell prostaglandin generation.

Received for publication, February 21, 2007 , and in revised form, September 13, 2007.

^* This work was funded by a Biotechnology and Biological Sciences Research Council Ph.D. studentship (to S. P. H.), a Yorkshire Cancer Research pump priming grant (to S. P. H. and J. H. W.), a British Heart Foundation project grant (to S. P. and J. H. W.), and a Wellcome Trust project grant (to J. H. W. and S. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-6.

¹ To whom correspondence should be addressed: Faculty of Biological Sciences, Institute of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom. Tel.: 44-113-3433119; Fax: 44-113-3433167; E-mail: j.h.walker{at}leeds.ac.uk.

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