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Papers In Press, published online ahead of print May 6, 2003
Division of Endocrinology & Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908
Corresponding Author: cch6n{at}virginia.edu
Atherosclerosis is a major complication of diabetes. Up to 16 weeks of age, db/db mice are insulin resistant and hyperglycemic, and are a good model of Type 2 diabetes. After 16 weeks of age, the mice develop pancreatic beta cell failure that progresses to a Type 1 diabetes phenotype. We have shown that glucose increases 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 (12SHETE) and 13S-hydroxyoctadecaenoic acid (13SHODE) in vivo compared to C57BLKS/J mice. Using isolated primary aortic EC from db/db mice and WEHI78/24 mouse monocytes in adhesion assays, we found increased WEHI monocyte adhesion to db/db EC (14±2 monos/field for db/db EC versus 4±1 monos/field for C57BLKS/J EC, p<0.002). Thus, EC from db/db mice appear to be “pre-activated” to bind monocytes. Analysis of db/db EC revealed a 2-fold elevation in 12/15LO protein compared to C57BLKS/J EC. To determine that 12/15LO products were responsible for the increased monocyte adhesion observed with db/db EC, 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-a-cyanocinnamate (CDC). Treatment of db/db EC for 48h with AdRZ or 4h with 10mM CDC 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 found that adhesion of monocytes to diabetic db/db EC was mediated by interactions of
J. Biol. Chem, 10.1074/jbc.M301175200
Submitted on February 3, 2003
Revised on April 11, 2003
Accepted on May 6, 2003
Increased production of 12/15 lipoxygenase eicosanoids accelerates monocyte:Endothelial interactions in diabetic db/db mice
4
1 integrin on monocytes with endothelial VCAM-1 and CS-1 fibronectin and interactions of 2 integrins with endothelial ICAM-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.
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