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J. Biol. Chem., Vol. 283, Issue 49, 33975-33987, December 5, 2008

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Smooth Muscle Cell Arachidonic Acid Release, Migration, and Proliferation Are Markedly Attenuated in Mice Null for Calcium-independent Phospholipase A₂β^*

Sung Ho Moon, Christopher M. Jenkins, David J. Mancuso, John Turk^¶, and Richard W. Gross^||**1

From the Divisions of Bioorganic Chemistry and Molecular Pharmacology, ^¶Endocrinology, Metabolism, and Lipid Research, Departments of Medicine and ^||Molecular Biology & Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110 and the ^**Department of Chemistry, Washington University, St. Louis, Missouri 63130

Pharmacologic evidence suggests that the lipid products generated by one or more calcium-independent phospholipases A₂ (iPLA₂s) participate in the regulation of vascular tone through smooth muscle cell (SMC) Ca²⁺ signaling and the release of arachidonic acid. However, the recent identification of new members of the iPLA₂ family, each inhibitable by (E)-6-(bromomethylene)-3-(1-naphthalenyl)-2H-tetrahydropyran-2-one, has rendered definitive identification of the specific enzyme(s) mediating these processes difficult. Accordingly, we used iPLA₂β^–/– mice to demonstrate that iPLA₂β is responsible for the majority of thapsigargin and ionophore (A23187 [GenBank] )-induced arachidonic acid release from SMCs. Both thapsigargin and A23187 [GenBank] stimulated robust [³H]arachidonate (AA) release from wild-type aortic SMCs that was dramatically attenuated in iPLA₂β^–/– mice (>80% reduction at 5 min; p < 0.01). Moreover, iPLA₂β^–/– mice displayed defects in SMC Ca²⁺ homeostasis and decreased SMC migration and proliferation in a model of vascular injury. Ca²⁺-store depletion resulted in the rapid entry of external Ca²⁺ into wild-type aortic SMCs that was significantly slower in iPLA₂β-null cells (p < 0.01). Furthermore, SMCs from iPLA₂β-null mesenteric arterial explants demonstrated decreased proliferation and migration. The defects in migration and proliferation in iPLA₂β-null SMCs were restored by 2 µM AA. Remarkably, the cyclooxygenase-2-specific inhibitor, NS-398, prevented AA-induced rescue of SMC migration and proliferation in iPLA₂β^–/– mice. Moreover, PGE₂ alone rescued proliferation and migration in iPLA₂β^–/– mice. We conclude that iPLA₂β is an important mediator of AA release and prostaglandin E₂ production in SMCs, modulating vascular tone, cellular signaling, proliferation, and migration.

Received for publication, July 29, 2008 , and in revised form, October 7, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants 5PO1HL57278-10 and 2RO1HL41250-13. 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.

¹ To whom correspondence should be addressed: Division of Bioorganic Chemistry and Molecular Pharmacology, Washington University School of Medicine, 660 South Euclid Ave., Campus Box 8020, St. Louis, MO 63110. Tel.: 314-362-2690; Fax: 314-362-1402; E-mail: rgross{at}wustl.edu.

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