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J. Biol. Chem., Vol. 280, Issue 24, 22706-22714, June 17, 2005

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Reactive Carbonyls and Polyunsaturated Fatty Acids Produce a Hydroxyl Radical-like Species

A POTENTIAL PATHWAY FOR OXIDATIVE DAMAGE OF RETINAL PROTEINS IN DIABETES^*

Subramaniam Pennathur, Yasuo Ido¶||, Jozsef I. Heller**, Jaeman Byun, Ratna Danda, Pablo Pergola, Joseph R. Williamson¶, and Jay W. Heinecke¶¶

From the Department of Medicine, University of Washington, Seattle Washington 98195, ^¶Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, ^**Department of Pathology, Rush University, Chicago, Illinois 60612, and Department of Medicine, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, Texas 78229

The pattern of oxidized amino acids in aortic proteins of nonhuman primates suggests that a species resembling hydroxyl radical damages proteins when blood glucose levels are high. However, recent studies argue strongly against a generalized increase in diabetic oxidative stress, which might instead be confined to the vascular wall. Here, we describe a pathway for glucose-stimulated protein oxidation and provide evidence of its complicity in diabetic microvascular disease. Low density lipoprotein incubated with pathophysiological concentrations of glucose became selectively enriched in ortho-tyrosine and meta-tyrosine, implicating a hydroxyl radical-like species in protein damage. Model system studies demonstrated that the reaction pathway requires both a reactive carbonyl group and a polyunsaturated fatty acid, involves lipid peroxidation, and is blocked by the carbonyl scavenger aminoguanidine. To explore the physiological relevance of the pathway, we used mass spectrometry and high pressure liquid chromatography to quantify oxidation products in control and hyperglycemic rats. Hyperglycemia raised levels of ortho-tyrosine, meta-tyrosine, and oxygenated lipids in the retina, a tissue rich in polyunsaturated fatty acids. Rats that received aminoguanidine did not show this increase in protein and lipid oxidation. In contrast, rats with diet-induced hyperlipidemia in the absence of hyperglycemia failed to exhibit increased protein and lipid oxidation products in the retina. Our observations suggest that generation of a hydroxyl radical-like species by a carbonyl/polyunsaturated fatty acid pathway might promote localized oxidative stress in tissues vulnerable to diabetic damage. This raises the possibility that antioxidant therapies that specifically inhibit the pathway might delay the vascular complications of diabetes.

Received for publication, January 24, 2005 , and in revised form, March 8, 2005.

^* This research was supported in part by Grants DK02456, AG021191, EY06600, HL39934, DK20579, and P30ES07033 from the National Institutes of Health and by the Kilo Research Foundation (St. Louis, MO). 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.

Supported by Career Development Award 2-2003-149 from the Juvenile Diabetes Research Foundation.

^|| Current address: Dept. of Medicine, Boston University, Boston, MA 02118.

Supported by a George O'Brien Kidney Research Center grant, a grant-in-aid from the American Heart Association, Texas affiliate, and the Department of Veterans Affairs Research Enhancement Award Program (REAP).

^¶¶ To whom correspondence should be addressed: Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, WA 98195. Fax: 206-685–8346; E-mail: heinecke{at}u.washington.edu.

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