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J. Biol. Chem., Vol. 281, Issue 42, 31298-31308, October 20, 2006

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Phospholipid Hydroxyalkenals, a Subset of Recently Discovered Endogenous CD36 Ligands, Spontaneously Generate Novel Furan-containing Phospholipids Lacking CD36 Binding Activity in Vivo^*

Shengqiang Gao¹, Renliang Zhang, Michael E. Greenberg, Mingjiang Sun, Xi Chen^¶, Bruce S. Levison, Robert G. Salomon^¶, and Stanley L. Hazen^||2

From the Departments of Cell Biology and ^||Cardiovascular Medicine and the Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic Foundation, Cleveland, Ohio 44195 and the ^¶Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106

We recently identified a novel family of oxidized choline glycerophospholipid (oxPC) molecular species enriched in atheroma that serve as endogenous ligands for the scavenger receptor CD36 (oxPC_CD36), facilitating macrophage cholesterol accumulation and foam cell formation (Podrez, E. A., Poliakov, E., Shen, Z., et al. (2002) J. Biol. Chem. 277, 38517–38523). A high affinity CD36 recognition motif was defined within oxPC_CD36, an oxidatively truncated sn-2 acyl group with a terminal -hydroxy (or oxo)-,-unsaturated carbonyl. The fate of these species once formed in vivo is unknown. Here we show that a subset of oxPC_CD36, a phosphatidylcholine molecular species possessing sn-2 esterified fatty acyl hydroxyalkenal groups, can undergo a slow intramolecular cyclization and dehydration reaction to form novel oxPC species possessing a sn-2 acyl group that incorporates a terminal furyl moiety (oxPC-furan). Using high performance liquid chromatography with on-line tandem mass spectrometry in combination with unambiguous organic synthesis, we confirm that oxPC-furans, ultimately derived from phospholipids with sn-2 esterified docosahexaenoic, arachidonic, or linoleic acids, are formed during exposure of model membranes and isolated lipoproteins to physiological oxidant systems. In vivo generation of oxPC-furans at sites of enhanced oxidant stress is also demonstrated, such as within brain tissues following cerebral ischemia. Cell binding studies reveal that in contrast to their oxPC_CD36 precursors, oxPC-furans lack CD36 binding activity. Taken together, the present studies identify oxPC-furans as a novel family of oxidized phospholipids that are formed in vivo from phospholipid hydroxyalkenals but that lack CD36 binding activity.

Received for publication, April 27, 2006 , and in revised form, July 24, 2006.

^* This work was supported by National Institutes of Health Grants P01 HL076491, P01 HL077107, HL70621, HL61878, GM21249, and HL53315 and supported in part by Cleveland Clinic Foundation General Clinical Research Center Grant M01 RR018390. 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 Supported in part by a fellowship from the American Heart Association.

² To whom correspondence should be addressed: Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic Foundation, 9500 Euclid Ave., NE-10, Cleveland, OH 44195. Tel.: 216-445-9763; Fax: 216-636-0392; E-mail: hazens{at}ccf.org.

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