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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1097.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Increased ADAM17 mRNA Expression and Activity Is Associated With Atherosclerosis Resistance in LDL-Receptor Deficient Mice

Lesca M. Holdt; Joachim Thiery; Jan L. Breslow; Daniel Teupser

From the Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (L.M.H., J.T., D.T.), University Hospital Leipzig, Germany; and the Laboratory of Biochemical Genetics and Metabolism (J.L.B.), The Rockefeller University, New York.

Correspondence to Dr Daniel Teupser, Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Liebigstr.27, 04103 Leipzig, Germany. E-mail teupser{at}medizin.uni-leipzig.de

Background— We have previously identified an atherosclerosis quantitative trait locus (QTL) on mouse chromosome (Chr) 12 in an F2-intercross of atherosclerosis-resistant FVB and atherosclerosis-susceptible C57BL/6 (B6) mice on the LDL-receptor deficient (LDL^–/–) background. The aim of the present study was to identify potentially causative genes at this locus.

Methods and Results— Expression QTL (eQTL) analysis of candidate genes in livers of F2-mice revealed that a disintegrin and metalloproteinase 17 (ADAM17) mRNA expression mapped to the physical position of ADAM17 on proximal Chr12 (21.6 Mb, LOD 3.3) and colocalized with the atherosclerosis QTL. The FVB allele was associated with significantly higher ADAM17 mRNA expression (39%) than the B6 allele. Likewise, ADAM17 mRNA levels in the parental strains were significantly elevated in FVB.LDLR^–/– compared to B6.LDLR^–/– mice in liver, macrophages, and aorta (68%, 58%, and 32%, respectively). Reporter gene assays revealed a genetic variant that might explain these expression differences. Moreover, FVB.LDLR^–/– macrophages showed 5-fold increased PMA-induced shedding of tumor necrosis factor (TNF)- and 32% increased release of TNF-receptor I compared to B6.LDLR^–/–. The atherosclerosis locus and expression differences were confirmed in Chr12 interval-specific congenic mice.

Conclusion— Our data provide functional evidence for ADAM17 as a candidate gene of atherosclerosis susceptibility at the murine Chr12 QTL.

In previous work, we have identified an atherosclerosis susceptibility quantitative trait locus (QTL) on mouse chromosome 12 in an F2-intercross of LDL receptor–deficient FVB and C57BL/6 mice. Using expression QTL mapping and functional assays, we identified the metalloproteinase ADAM17 as a candidate gene of atherosclerosis susceptibility at this locus.

Key Words: atherosclerosis • genetics • ADAM17 • mouse models • expression QTL

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