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J. Biol. Chem., Vol. 279, Issue 50, 52425-52436, December 10, 2004

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Anti-apoptotic Actions of the Platelet-activating Factor Acetylhydrolase I ₂ Catalytic Subunit^*

Fanny Bonin¶, Scott D. Ryan, Lamiaa Migahed||, Fan Mo||, Jessica Lallier, Doug J. Franks**, Hiroyuki Arai, and Steffany A. L. Bennett

From the Neural Regeneration Laboratory, Department of Biochemistry, Microbiology, and Immunology and the ^**Department of Pathology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada and Graduate School of Pharmaceutical Sciences, University of Tokyo, 3-1, Hongo-7, Bunkyo-ku, Tokyo 113-0033, Japan

Platelet-activating factor (PAF) is an important mediator of cell loss following diverse pathophysiological challenges, but the manner in which PAF transduces death is not clear. Both PAF receptor-dependent and -independent pathways are implicated. In this study, we show that extracellular PAF can be internalized through PAF receptor-independent mechanisms and can initiate caspase-3-dependent apoptosis when cytosolic concentrations are elevated by 15 pM/cell for 60 min. Reducing cytosolic PAF to less than 10 pM/cell terminates apoptotic signaling. By pharmacological inhibition of PAF acetylhydrolase I and II (PAF-AH) activity and down-regulation of PAF-AH I catalytic subunits by RNA interference, we show that the PAF receptor-independent death pathway is regulated by PAF-AH I and, to a lesser extent, by PAF-AH II. Moreover, the anti-apoptotic actions of PAF-AH I are subunit-specific. PAF-AH I ₁ regulates intracellular PAF concentrations under normal physiological conditions, but expression is not sufficient to reduce an acute rise in intracellular PAF levels. PAF-AH I ₂ expression is induced when cells are deprived of serum or exposed to apoptogenic PAF concentrations limiting the duration of pathological cytosolic PAF accumulation. To block PAF receptor-independent death pathway, we screened a panel of PAF antagonists (CV-3988, CV-6209, BN 52021, and FR 49175). BN 52021 and FR 49175 accelerated PAF hydrolysis and inhibited PAF-mediated caspase 3 activation. Both antagonists act indirectly to promote PAF-AH I ₂ homodimer activity by reducing PAF-AH I ₁ expression. These findings identify PAF-AH I ₂ as a potent anti-apoptotic protein and describe a new means of pharmacologically targeting PAF-AH I to inhibit PAF-mediated cell death.

Received for publication, September 23, 2004

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY225592.

^* This work was supported in part by grants from the Alzheimer Society of Canada, Alzheimer Society of Saskatchewan, and the Canadian Institute of Health Research Joint Initiative (to S. A. L. B.). 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.

Both authors contributed equally to this work.

^¶ Supported by a graduate studentship from the Scottish Rite/Roher Foundation.

^|| Supported by a National Research Council undergraduate research award.

Ontario Mental Health Foundation Intermediate Investigator and a Canadian Institute of Health Research New Investigator. To whom correspondence should be addressed: Neural Regeneration Laboratory, Dept. of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada. Tel.: 613-562-5600 (Ext. 8372); Fax: 613-562-5452; E-mail: sbennet{at}uottawa.ca.

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