Soluble epoxide hydrolase is a susceptibility factor for heart failure in a rat model of human disease

被引：150

作者：

Monti, Jan ^{[1
,2
]}

Fischer, Judith ^{[1
]}

Paskas, Svetlana ^{[1
]}

Heinig, Matthias ^{[1
,3
]}

Schulz, Herbert ^{[1
]}

Goesele, Claudia ^{[1
]}

Heuser, Arnd ^{[1
,2
]}

Fischer, Robert ^{[1
,2
]}

Schmidt, Cosima ^{[1
]}

Schirdewan, Alexander ^{[2
]}

Gross, Volkmar ^{[1
]}

Hummel, Oliver ^{[1
]}

Maatz, Henrike ^{[1
]}

Patone, Giannino ^{[1
]}

Saar, Kathrin ^{[1
]}

Vingron, Martin ^{[3
]}

Weldon, Steven M. ^{[4
]}

Lindpaintner, Klaus ^{[5
]}

Hammock, Bruce D. ^{[6
,7
,8
]}

Rohde, Klaus ^{[1
]}

Dietz, Rainer ^{[1
,2
]}

Cook, Stuart A. ^{[9
]}

Schunck, Wolf-Hagen ^{[1
]}

Luft, Friedrich C. ^{[1
,10
]}

Hubner, Norbert ^{[1
]}

机构：

[1] Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany

[2] Charite Univ Med Berlin, HELIOS, Franz Volhard Clin, Dept Clin & Mol Cardiol, D-13125 Berlin, Germany

[3] Max Planck Inst Mol Genet, Dept Bioinformat, D-14195 Berlin, Germany

[4] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA

[5] F Hoffmann La Roche, CH-4070 Basel, Switzerland

[6] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA

[7] Univ Calif Davis, Dept Nutr, Davis, CA 95616 USA

[8] Univ Calif Davis, Canc Res Ctr, Davis, CA 95616 USA

[9] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW3 6LY, England

[10] Charite Univ Med Berlin, HELIOS, Franz Volhard Clin, Dept Nephrol Hypertens, D-13125 Berlin, Germany

来源：

NATURE GENETICS | 2008年 / 40卷 / 05期

基金：

英国医学研究理事会;

关键词：

D O I：

10.1038/ng.129

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We aimed to identify genetic variants associated with heart failure by using a rat model of the human disease. We performed invasive cardiac hemodynamic measurements in F-2 crosses between spontaneously hypertensive heart failure ( SHHF) rats and reference strains. We combined linkage analyses with genome-wide expression profiling and identified Ephx2 as a heart failure susceptibility gene in SHHF rats. Specifically, we found that cis variation at Ephx2 segregated with heart failure and with increased transcript expression, protein expression and enzyme activity, leading to a more rapid hydrolysis of cardioprotective epoxyeicosatrienoic acids. To confirm our results, we tested the role of Ephx2 in heart failure using knockout mice. Ephx2 gene ablation protected from pressure overload-induced heart failure and cardiac arrhythmias. We further demonstrated differential regulation of EPHX2 in human heart failure, suggesting a cross-species role for Ephx2 in this complex disease.

引用

页码：529 / 537

页数：9

共 49 条

[1] Angiotensin II up-regulates soluble epoxide hydrolase in vascular endothelium in vitro and in vivo [J].