title: Soluble epoxide hydrolase is a susceptibility factor for heart failure in a rat model of human disease.
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 F2 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.
authors.affiliation: Max-Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Monti
authors.forename: Judith
authors.initials: J
authors.lastname: Fischer
authors.forename: Svetlana
authors.initials: S
authors.lastname: Paskas
authors.forename: Matthias
authors.initials: M
authors.lastname: Heinig
authors.forename: Herbert
authors.initials: H
authors.lastname: Schulz
authors.forename: Claudia
authors.initials: C
authors.lastname: Gösele
authors.forename: Arnd
authors.initials: A
authors.lastname: Heuser
authors.forename: Robert
authors.initials: R
authors.lastname: Fischer
authors.forename: Cosima
authors.initials: C
authors.lastname: Schmidt
authors.forename: Alexander
authors.initials: A
authors.lastname: Schirdewan
authors.forename: Volkmar
authors.initials: V
authors.lastname: Gross
authors.forename: Oliver
authors.initials: O
authors.lastname: Hummel
authors.forename: Henrike
authors.initials: H
authors.lastname: Maatz
authors.forename: Giannino
authors.initials: G
authors.lastname: Patone
authors.forename: Kathrin
authors.initials: K
authors.lastname: Saar
authors.forename: Martin
authors.initials: M
authors.lastname: Vingron
authors.forename: Steven M
authors.initials: SM
authors.lastname: Weldon
authors.forename: Klaus
authors.initials: K
authors.lastname: Lindpaintner
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Klaus
authors.initials: K
authors.lastname: Rohde
authors.forename: Rainer
authors.initials: R
authors.lastname: Dietz
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Cook
authors.forename: Wolf-Hagen
authors.initials: WH
authors.lastname: Schunck
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D004195:Disease Models, Animal; D004851:Epoxide Hydrolases / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006333:Heart Failure / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D040641:Quantitative Trait Loci; D051381:Rats / Q000235:genetics*; D011922:Rats, Mutant Strains; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D018808:Transcription Factor AP-1; D004851:Epoxide Hydrolases; C506428:EPHX2 protein, human; C529022:EPHX2 protein, rat