International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


Oral Presentation

Monday 18 November

21:00 - 21:15 HRS

IDENTIFICATION OF 5-LIPOXYGENASE AS A MAJOR GENE CONTRIBUTING TO ATHEROSCLEROSIS SUSCEPTIBILITY IN MICE

M Mehrabian
UCLA

Co-Authors: 1) Allayee H, 1)Wong J, 2)Shih W, 1)Wang X-P, 1)Shaposhnik Z, 3)Funk CD, 1) Lusis AJ
Institutions: 1) UCLA  2) University of Virginia 3) University of Penn

We identified a locus on mouse chromosome 6 that dramatically reduces aortic lesion formation in an intercross between the susceptible strain, C57BL6/J and the resistant strain, CAST/Ei.  We constructed a congenic strain (CON6) in which the chromosome 6 interval from CAST was transferred onto a hypercholesterolemic LDLR-/- background.   CON6 was almost completely resistant to diet induced atherosclerosis, even under conditions of extreme hyperlipidemia.  Studies of genes in the region indicated that 5-lipoxygenase (5LO) expression was decreased by ~5-fold, relative to B6 in CON6.  5LO is rate limiting for synthesis of leukotrienes (LT), inflammatory lipids biosynthesized from arachidonic acid.  LTB4 levels were only 2% in CAST when compared with B6 controls.  There were two amino acid differences between the two strains at positions 645 (CAST/Val; B6/Ile) and 646 (CAST/Ile; B6/Val) located within a region conserved among proteins that translocate from the cytosol to the nucleus. We bred 5LO-/- onto an LDLR-/- background. These mice showed a dramatic decrease in aortic lesion development, similar to the CON6 mice.  5-LO was abundantly expressed in atherosclerotic lesions, co-localizing with a subset of macrophages overlaying the necrotic core.  Bone marrow from 5LO+/-/LDLR-/- was transplanted into LDL receptor null mice; there was a significant reduction in atherogenesis, suggesting that the macrophage 5LO is in part responsible for the effect on atherosclerosis.  Finally, we have found that a polymorphism of the human 5LO gene (allele 3) is strongly associated with atherogenesis.  Our results indicate that 5LO metabolites such as leukotrienes play an important role in atherosclerosis.


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