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

Official URL:https://doi.org/10.1038/ng.129
PubMed:View item in PubMed
Creators Name:Monti, J. and Fischer, J. and Paskas, S. and Heinig, M. and Schulz, H. and Goesele, C. and Heuser, A. and Fischer, R. and Schmidt, C. and Schirdewan, A. and Gross, V. and Hummel, O. and Maatz, H. and Patone, G. and Saar, K. and Vingron, M. and Weldon, S.M. and Lindpaintner, K. and Hammock, B.D. and Rohde, K. and Dietz, R. and Cook, S.A. and Schunck, W.H. and Luft, F.C. and Huebner, N.
Journal Title:Nature Genetics
Journal Abbreviation:Nat Genet
Volume:40
Number:5
Page Range:529-537
Date:May 2008
Keywords:Chromosome Mapping, Animal Disease Models, Epoxide Hydrolases, Gene Expression Profiling, Genetic Predisposition to Disease, Heart Failure, Hypertension, Linkage, Myocardium, Genetic Polymorphism, Single Nucleotide Polymorphism, Genetic Promoter Regions, Quantitative Trait Loci, DNA Sequence Analysis, Sequence Deletion, Transcription Factor AP-1, Animals, Mice, Rats
Abstract: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.
ISSN:1061-4036
Publisher:Nature Publishing Group (U.S.A.)
Item Type:Article

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