This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 26/6/1260    most recent 01.ATV.0000217909.09198.d6v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bolick, D. T. Articles by Hedrick, C. C. Search for Related Content PubMed PubMed Citation Articles by Bolick, D. T. Articles by Hedrick, C. C. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Related Collections Related Article

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1260.)
© 2006 American Heart Association, Inc.

Vascular Biology

12/15 Lipoxygenase Mediates Monocyte Adhesion to Aortic Endothelium in Apolipoprotein E–Deficient Mice Through Activation of RhoA and NF-B

David T. Bolick; Suseela Srinivasan; Angela Whetzel; Lauren C. Fuller; Catherine C. Hedrick

From Cardiovascular Research Center, University of Virginia, Charlottesville.

Correspondence to Catherine C. Hedrick, PhD, Cardiovascular Research Center, University of Virginia, PO Box 801394, 415 Lane Rd; MR5 Rm G123, Charlottesville, VA 22908. E-mail cch6n{at}virginia.edu

Objectives— 12/15 lipoxygenase (12/15LO) has been implicated as a mediator of inflammation and atherosclerosis. In the current study, we identified mechanisms through which 12/15LO mediates monocyte:endothelial interactions in vivo in apolipoprotein E-deficient mice (apoEKO), a well-characterized mouse model of atherosclerosis.

Methods and Results— In apoEKO mice that are also deficient in 12/15LO (doubleKO), monocyte adhesion to aorta in vivo was reduced by 95% in doubleKO mice compared with apoEKO mice. Inhibition of 12/15LO in apoEKO mice in vivo using CDC (Cinnamyl-3,4-Dihydroxy-a-Cyanocinnamate) prevented monocyte adhesion to aortic endothelium in apoEKO mice. Aortic endothelium of apoEKO mice had significant activation of rhoA compared with doubleKO aortic endothelium. Further, apoEKO aorta displayed significant activation of NF-B. DoubleKO aorta displayed little nuclear localization of NF-B. Finally, we found significant upregulation of intercellular adhesion molecule-1 (ICAM-1) on apoEKO aortic endothelium compared with doubleKO endothelium. Inhibition of rhoA and PKC significantly reduced NF-B activation, ICAM-1 induction, and monocyte adhesion to aorta.

Conclusions— We conclude that 12/15LO products activate endothelial rhoA and PKC. Activation of rhoA and PKC cause activation and translocation of NF-B to the nucleus, which, in turn, results in induction of ICAM-1. Induction of ICAM-1 on aortic endothelium stimulates monocyte:endothelial adhesion in vivo in apoEKO mice.

L12/15 lipoxygenase (12/15LO) products activate endothelial rhoA and PKC. Activation of rhoA and PKC causes activation and translocation of NF-B to the nucleus, which, in turn, results in induction of ICAM-1. Induction of ICAM-1 on aortic endothelium stimulates monocyte:endothelial adhesion in vivo in apoEKO mice.

Key Words: lipoxygenase • NF-B • ICAM-1 • endothelium

Related Article:

Lipoxygenase Pathways as Mediators of Early Inflammatory Events in Atherosclerosis

Colin D. Funk
Arterioscler. Thromb. Vasc. Biol. 2006 26: 1204-1206. [Full Text] [PDF]

This article has been cited by other articles:

				R. A. Gubitosi-Klug, R. Talahalli, Y. Du, J. L. Nadler, and T. S. Kern 5-Lipoxygenase, but Not 12/15-Lipoxygenase, Contributes to Degeneration of Retinal Capillaries in a Mouse Model of Diabetic Retinopathy Diabetes, May 1, 2008; 57(5): 1387 - 1393. [Abstract] [Full Text] [PDF]

				D. T. Bolick, A. M. Whetzel, M. Skaflen, T. L. Deem, J. Lee, and C. C. Hedrick Absence of the G Protein-Coupled Receptor G2A in Mice Promotes Monocyte/Endothelial Interactions in Aorta Circ. Res., March 2, 2007; 100(4): 572 - 580. [Abstract] [Full Text] [PDF]

				A. M. Whetzel, D. T. Bolick, S. Srinivasan, T. L. Macdonald, M. A. Morris, K. Ley, and C. C. Hedrick Sphingosine-1 Phosphate Prevents Monocyte/Endothelial Interactions in Type 1 Diabetic NOD Mice Through Activation of the S1P1 Receptor Circ. Res., September 29, 2006; 99(7): 731 - 739. [Abstract] [Full Text] [PDF]

				C. D. Funk Lipoxygenase Pathways as Mediators of Early Inflammatory Events in Atherosclerosis. Arterioscler. Thromb. Vasc. Biol., June 1, 2006; 26(6): 1204 - 1206. [Full Text] [PDF]