Published online before print July 5, 2001, doi: 10.1161/hh1401.093458
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© 2001 American Heart Association, Inc.
Molecular Medicine |
Genetic Locus in Mice That Blocks Development of Atherosclerosis Despite Extreme Hyperlipidemia
From the Department of Medicine (M.M., J.W., X.W., Z.J., W.S., A.M.F., A.J.L.), Department of Microbiology, Immunology and Molecular Genetics (M.M., J.W., X.W., Z.J., W.S., A.J.L.), Department of Human Genetics (M.M., J.W., X.W., Z.J., W.S., A.J.L.), and Molecular Biology Institute (M.M., J.W., X.W., Z.J., W.S., A.J.L.), University of California, Los Angeles. Dr Mehrabian is now at Charles Drew University of Medicine and Science, Los Angeles, Calif.
Correspondence to Dr Aldons J. Lusis, Department of Medicine, 47-123 CHS, UCLA, Los Angeles, CA 90095. E-mail jlusis{at}mednet.ucla.edu
Abstract— The genes contributing to the common forms of atherosclerosis are largely unknown. One approach to dissecting complex traits such as atherosclerosis is to use animal models, such as the mouse, to map and characterize the genetic loci involved. We now report the identification of a locus for aortic lesion formation on mouse chromosome 6 that exhibits a highly significant lod score of 6.7 in a genetic cross between the susceptible strain, C57BL/6J, and the resistant strain, CAST/Ei. The locus was confirmed by constructing a congenic strain in which the chromosome 6 segment from CAST/Ei was transferred to a C57BL/6J background in a series of backcrosses. The congenic strain was almost completely resistant to diet-induced atherosclerosis. The chromosome 6 segment was also transferred onto the background of an LDL receptor–null mutation and resulted again in almost complete resistance to aortic lesion formation. This locus also influenced insulin levels but did not affect plasma lipoprotein levels, blood pressure, or body fat. The chromosome 6 gene, which we call Artles (for arterial lesions), did not affect endothelial cell responses to oxidized LDL, but lesion formation was partially reduced through bone marrow transplantation. The locus contains the candidate gene peroxisome proliferator–activated receptor-
, and the congenic mice exhibited significantly reduced expression of peroxisome proliferator–activated receptor-.
Key Words: congenic strains • insulin • peroxisome proliferator–activated receptor-&ggr • bone marrow transplantation • quantitative trait locus
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