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J. Biol. Chem., Vol. 278, Issue 28, 25369-25375, July 11, 2003

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Increased Production of 12/15 Lipoxygenase Eicosanoids Accelerates Monocyte/Endothelial Interactions in Diabetic db/db Mice^*

Melissa E. Hatley, Suseela Srinivasan, Kelly B. Reilly, David T. Bolick and Catherine C. Hedrick 

From the Division of Endocrinology and Metabolism and Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia 22908

Atherosclerosis is a major complication of diabetes. Up to 16 weeks of age, the db/db mouse is insulin-resistant and hyperglycemic and is a good model of Type 2 diabetes. After 16 weeks of age, the mice develop pancreatic beta cell failure that can progress to a Type 1 diabetes phenotype. We have previously shown that glucose increases production of endothelial 12/15 lipoxygenase (12/15LO) products in vitro. In young 10-week-old Type 2 diabetic db/db mice, we found significant elevations in levels of urinary 12/15LO products, 12S-hydroxyeicosatetraenoic acid (12S-HETE) and 13S-hydroxyoctadecaenoic acid (13S-HODE) in vivo compared with C57BLKS/J mice. Using isolated primary aortic endothelial cells (ECs) from db/db mice and WEHI78/24 mouse monocyte cells in static adhesion assays, we found increased WEHI monocyte adhesion to db/db ECs (14 ± 2 monocytes/field for db/db ECs versus 4 ± 1 monocytes/field for C57BLKS/J ECs, p < 0.002). Thus, ECs from db/db mice appear to be "pre-activated" to bind monocytes. Analysis of db/db ECs revealed a 2-fold elevation in 12/15LO protein compared with C57BLKS/J EC. To determine that 12/15LO products were responsible for the increased monocyte adhesion observed with db/db ECs, we inhibited expression of murine 12/15LO using either an adenovirus expressing a ribozyme to 12/15LO (AdRZ) or with the 12/15LO inhibitor cinnamyl-3,4-dihydroxy--cyanocinnamate. Treatment of db/db ECs for 48 h with AdRZ or 4 h with 10 µM cinnamyl-3,4-dihydroxy--cyanocinnamate significantly reduced monocyte adhesion to db/db endothelium (p < 0.009). Thus, inhibition of the murine 12/15LO in db/db mice significantly reduced monocyte/endothelial interactions. We also found that adhesion of monocytes to diabetic db/db ECs was mediated by interactions of ₄₁ integrin on monocytes with endothelial vascular cell adhesion molecule 1 and connecting segment 1 fibronectin and interactions of ₂ integrins with endothelial intercellular adhesion molecule 1. In summary, regulation of the 12/15LO pathway is important for mediating early vascular changes in diabetes. Modulation of the 12/15LO pathway in the vessel wall may provide therapeutic benefit for early vascular inflammatory events in diabetes.

Received for publication, February 3, 2003 , and in revised form, April 11, 2003.

^* This work was supported by National Institutes of Health Grant P01 HL55798-06 and grants from Parke-Davis/Pfizer (Atorvastatin Research Award, to C. C. H.), the Jeffress Memorial Trust of Virginia (to C. C. H.), and the American Heart Association (Mid-Atlantic Affiliate, to C. C. H.). 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.

To whom correspondence should be addressed: Cardiovascular Research Center, University of Virginia, P. O. Box 801394, 415 Lane Rd., MR5 Rm. G123, Charlottesville, VA 22908. Tel.: 434-982-4065; Fax: 434-924-2828; E-mail: cch6n{at}virginia.edu.

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