Genetic Locus in Mice That Blocks Development of Atherosclerosis Despite Extreme Hyperlipidemia

Abstract

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-␥. A therosclerosis is a disease of the large arteries that is the primary cause of heart disease and stroke. A large number of risk factors for the disease have been identified through epidemiological studies, including genetic traits, such as elevated cholesterol, elevated blood pressure, reduced HDL levels, and male sex, as well as environmental factors, such as smoking and a high-fat diet. Altogether, these risk factors do not appear to fully explain atherosclerosis. The search for genes contributing to the common multifactorial forms of atherosclerosis has been only modestly successful, with a major problem being the very complex etiology of the disease. 1 One potentially powerful approach to understanding the genetic factors in the disease is the analysis of animal models such as mice. Inbred strains of mice differ greatly in susceptibility to the development of atherosclerotic lesions when maintained on high-fat diets; they also differ regarding the background of hyperlipidemia-inducing null mutations of apolipoprotein E or the LDL receptor (LDLR). [2][3][4][5][6][7] We now report the mapping and partial characterization of a genetic locus on chromosome 6 that blocks the development of both early and advanced atherosclerotic lesions. A congenic strain carrying the locus exhibited little or no lesion formation even under conditions of extreme hyperlipidemia resulting from an LDLR mutation. The locus did not affect several risk factors normally associated with atherosclerosis, including LDL and VLDL levels, HDL levels, and blood pressure, suggesting the involvement of a novel pathway fo...

Complex Inheritance of the 5-Lipoxygenase Locus Influencing Atherosclerosis in Mice

“…Moreover, resistance to atherosclerosis by the chromosome 6 congenic region or the 5LO knockout was mediated, in part, by bone-marrow-derived cells as judged by bone marrow transplantation experiments, consistent with a role for 5LO (Mehrabian et al 2001(Mehrabian et al , 2002. From this work, we concluded that 5LO is a primary candidate gene in the CON6 locus (Mehrabian et al 2002).…”

“…To generate chromosome 6 subcongenic Ldlr À/À mice, B6.CAST chromosome 6 congenic mice containing the lowdensity-lipoprotein-receptor null mutation (referred to here as ''CON6.Ldlr (Mehrabian et al 2001) …”

“…Several years ago, we reported the presence of linkage between the middle/distal segment of chromosome 6 and the size of atheroma (LOD ¼ 6.7) in 250 F 2 mice generated from the athero-susceptible C57BL/6J (B6) and athero-resistant CAST/Ei (CAST) parental strains (Mehrabian et al 2001). In this cross, the CAST allele was associated with decreased aortic lesions.…”

“…The genetic effect of the chromosome 6 locus on lesion size was subsequently confirmed by introgressing this locus from CAST onto the B6 background and analyzing the lesion area in the congenic strain (CON6). Similarly, when CON6 mice on the low-density receptor null background (Ldlr À/À ) were fed with a high-fat diet, they had reduced lesion size compared with the B6.Ldlr À/À mice despite hypercholesterolemia, suggesting that this locus influences lesion development by a mechanism distinct from lipid metabolism (Mehrabian et al 2001).…”

Using Mice to Dissect Genetic Factors in Atherosclerosis

“…Initially, Artles was identified in an F 2 cross between inbred strains C57BL/6J and CAST/Ei and exhibited a highly significant LOD score of 6.7 ( Figure 1B). 36 Interestingly, there was coincident linkage of insulin levels with this locus, raising the possibility that the underlying gene has pleiotropic effects on atherosclerosis and other related metabolic traits ( Figure 1B). Subsequently, a congenic strain was developed to confirm the functional importance of the QTL and to identify the underlying gene that causes resistance to lesion formation.…”