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J. Biol. Chem., Vol. 279, Issue 51, 53395-53406, December 17, 2004

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Aldose Reductase-catalyzed Reduction of Aldehyde Phospholipids^*

Sanjay Srivastava, Matthew Spite, John O. Trent, Matthew B. West, Yonis Ahmed, and Aruni Bhatnagar¶

From the Institute of Molecular Cardiology and the James Brown Cancer Center, Department of Medicine, University of Louisville, Louisville, Kentucky 40202

Oxidation of unsaturated phospholipids results in the generation of aldehyde side chains that remain esterified to the phospholipid backbone. Such "core" aldehydes elicit immune responses and promote inflammation. However, the biochemical mechanisms by which phospholipid aldehydes are metabolized or detoxified are not well understood. In the studies reported here, we examined whether aldose reductase (AR), which reduces hydrophobic aldehydes, metabolizes phospholipid aldehydes. Incubation with AR led to the reduction of 5-oxovaleroyl, 7-oxo-5-heptenoyl, 5-hydroxy-6-oxo-caproyl, and 5-hydroxy-8-oxo-6-octenoyl phospholipids generated upon oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC). The enzyme also catalyzed the reduction of phospholipid aldehydes generated from the oxidation of 1-alkyl, and 1-alkenyl analogs of PAPC, and 1-palmitoyl-2-arachidonoyl phosphatidic acid or phosphoglycerol. Aldose reductase catalyzed the reduction of chemically synthesized 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphatidylcholine (POVPC) with a K_m of 10 µM. Addition of POVPC to the culture medium led to incorporation and reduction of the aldehyde in COS-7 and THP-1 cells. Reduction of POVPC in these cells was prevented by the AR inhibitors sorbinil and tolrestat and was increased in COS-7 cells overexpressing AR. Together, these observations suggest that AR may be a significant participant in the metabolism of several structurally diverse phospholipid aldehydes. This metabolism may be a critical regulator of the pro-inflammatory and immunogenic effects of oxidized phospholipids.

Received for publication, March 29, 2004 , and in revised form, September 28, 2004.

^* This work was supported in part by National Institutes of Health Grants HL55477, HL59378, ES11860 (to A. B.) and HL65618 (to S. S.). 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 Materials.

^¶ To whom correspondence should be addressed: Division of Cardiology, Dept. of Medicine, Delia Baxter Bldg., 580 S. Preston St., Room 421F, University of Louisville, Louisville, KY 40202. Tel.: 502-852-5966; Fax: 502-852-3663; E-mail: aruni{at}louisville.edu.

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