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Originally published In Press as doi:10.1074/jbc.M301175200 on May 6, 2003
J. Biol. Chem., Vol. 278, Issue 28, 25369-25375, July 11, 2003
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 4 1 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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Copyright © 2003 by the American Society for Biochemistry and Molecular Biology.
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