on September 25, 2008
Published online before print September 25, 2008, doi: 10.1161/ATVBAHA.108.176800
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Submitted on April 3, 2008
Accepted on September 15, 2008
Athsq1 Is an Atherosclerosis Modifier Locus With Dramatic Effects on Lesion Area and Prominent Accumulation of Versican
Sara Bretschger Seidelmann ;
From the Division of Molecular Medicine, Department of Medicine (S.B.S., C.K., N.P., J.M., S.S., R.L., J.Z., A.R.T., C.L.W.) and the Institute of Human Nutrition (S.B.S., C.K., J.M., S.S.), Columbia University, New York; Hope Heart Program (P.J., K.B., C.C., T.N.W.), Benaroya Research Institute at Virginia Mason, Seattle, Wash; the Laboratory of Biochemical Genetics and Metabolism (D.T., J.L.B.), The Rockefeller University, New York.
* To whom correspondence should be addressed. E-mail: cbw13{at}columbia.edu.
Objective—Susceptibility to atherosclerosis is genetically complex, and modifier genes that do not operate via traditional risk factors are largely unknown. A mouse genetics approach can simplify the genetic analysis and provide tools for mechanistic studies.
Methods and Results—We previously identified atherosclerosis susceptibility QTL (Athsq1) on chromosome 4 acting independently of systemic risk factors. We now report confirmation of this locus in congenic strains carrying the MOLF-derived susceptibility allele in the C57BL/6J-Ldlr-/- genetic background. Homozygous congenic mice exhibited up to 4.5-fold greater lesion area compared to noncongenic littermates (P<0.0001). Analysis of extracellular matrix composition revealed prominent accumulation of versican, a presumed proatherogenic matrix component abundant in human lesions but almost absent in the widely-used C57BL/6 murine atherosclerosis model. The results of a bone marrow transplantation experiment suggested that both accelerated lesion development and versican accumulation are mediated, at least in part, by macrophages. Interestingly, comparative mapping revealed that the Athsq1 congenic interval contains the mouse region homologous to a widely-replicated CHD locus on human chromosome 9p21.
Conclusion—These studies confirm the proatherogenic activity of a novel gene(s) in the MOLF-derived Athsq1 locus and provide in vivo evidence for a causative role of versican in lesion development.
Key words: atherosclerosis • congenic strain • genetics • extracellular matrix • mapping