Increased ADAM17 mRNA expression and activity is associated with atherosclerosis resistance in LDL-receptor deficient mice

被引：46

作者：

Holdt, Lesca M. ^{[1
]}

Thiery, Joachim ^{[1
]}

Breslow, Jan L. ^{[2
]}

Teupser, Daniel ^{[1
]}

机构：

[1] Univ Hosp Leipzig, Inst Lab Med Clin Chem & Mol Diagnost, D-04103 Leipzig, Germany

[2] Rockefeller Univ, Biochem Genet & Metab Lab, New York, NY 10021 USA

来源：

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY | 2008年 / 28卷 / 06期

关键词：

atherosclerosis; genetics; ADAM17; mouse models; expression QTL;

D O I：

10.1161/ATVBAHA.108.165654

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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)-alpha 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.

引用

页码：1097 / 1103

页数：7

共 35 条

[1] A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells [J].

Black, RA ;

Rauch, CT ;

Kozlosky, CJ ;

Peschon, JJ ;

Slack, JL ;

Wolfson, MF ;

Castner, BJ ;

Stocking, KL ;

Reddy, P ;

Srinivasan, S ;

Nelson, N ;

Boiani, N ;

Schooley, KA ;

Gerhart, M ;

Davis, R ;

Fitzner, JN ;

Johnson, RS ;

Paxton, RJ ;

March, CJ ;

Cerretti, DP .

NATURE, 1997, 385 (6618) :729-733

[2] Lesion progression and plaque composition are not altered in older apoE-/- mice lacking tumor necrosis factor-α receptor p55 [J].

Blessing, E ;

Bea, F ;

Kuo, CC ;

Campbell, LA ;

Chesebro, B ;

Rosenfeld, ME .

ATHEROSCLEROSIS, 2004, 176 (02) :227-232

[3] Inhibition of tumor necrosis factor-α reduces atherosclerosis in apolipoprotein E knockout mice [J].

Branén, L ;

Hovgaard, L ;

Nitulescu, M ;

Bengtsson, E ;

Nilsson, J ;

Jovinge, S .

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2004, 24 (11) :2137-2142

[4] The TNF alpha converting enzyme (TACE/ADAM17) is expressed in the atherosclerotic lesions of apolipoprotein E-deficient mice: Possible contribution to elevated plasma levels of soluble TNF alpha receptors [J].

Canault, Matthias ;

Peiretti, Franck ;

Kopp, Francis ;

Bonardo, Bernadette ;

Bonzi, Marie-France ;

Coudeyre, Jean-Christophe ;

Alessi, Marie-Christine ;

Juhan-Vague, Lrne ;

Nalbone, Gilles .

ATHEROSCLEROSIS, 2006, 187 (01) :82-91

[5] Decreased atherosclerosis in mice deficient in tumor necrosis factor-α receptor-II (p75) [J].

Chandrasekharan, Unni M. ;

Mavrakis, Lori ;

Smith, Jonathan D. ;

DiCorleto, Paul E. ;

Bonfield, Tracy L. .

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2007, 27 (03) :E16-E17

[6] Interleukin-1 receptor signaling mediates atherosclerosis associated with bacterial exposure and/or a high-fat diet in a murine apolipoprotein E heterozygote model - Pharmacotherapeutic implications [J].

Chi, HH ;

Messas, E ;

Levine, RA ;

Graves, DT ;

Amar, S .

CIRCULATION, 2004, 110 (12) :1678-1685

[7] A major role for VCAM-1, but not ICAM-1, in early atherosclerosis [J].

Cybulsky, MI ;

Iiyama, K ;

Li, HM ;

Zhu, SN ;

Chen, M ;

Iiyama, M ;

Davis, V ;

Gutierrez-Ramos, JC ;

Connelly, PW ;

Milstone, DS .

JOURNAL OF CLINICAL INVESTIGATION, 2001, 107 (10) :1255-1262

[8] Nuclear factor κB signaling in atherogenesis [J].

de Winther, MPJ ;

Kanters, E ;

Kraal, G ;

Hofker, MH .

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2005, 25 (05) :904-914

[9] TACE/ADAM-17 enzymatic activity is increased in response to cellular stimulation [J].

Doedens, JR ;

Mahimkar, RM ;

Black, RA .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2003, 308 (02) :331-338

[10] Single-nucleotide polymorphism genotyping by melting analysis of dual-labeled probes: Examples using factor V Leiden and prothrombin 20210A mutations [J].

El Housni, H ;

Heimann, P ;

Parma, J ;

Vassart, G .

CLINICAL CHEMISTRY, 2003, 49 (10) :1669-1672

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