Soluble epoxide hydrolase is a susceptibility factor for heart failure in a rat model of human disease.
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.
Monti
Jan
J
Max-Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
Fischer
Judith
J
Paskas
Svetlana
S
Heinig
Matthias
M
Schulz
Herbert
H
Gösele
Claudia
C
Heuser
Arnd
A
Fischer
Robert
R
Schmidt
Cosima
C
Schirdewan
Alexander
A
Gross
Volkmar
V
Hummel
Oliver
O
Maatz
Henrike
H
Patone
Giannino
G
Saar
Kathrin
K
Vingron
Martin
M
Weldon
Steven M
SM
Lindpaintner
Klaus
K
Hammock
Bruce D
BD
Rohde
Klaus
K
Dietz
Rainer
R
Cook
Stuart A
SA
Schunck
Wolf-Hagen
WH
Luft
Friedrich C
FC
Hubner
Norbert
N
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
D018808:Transcription Factor AP-1; D004851:Epoxide Hydrolases; C506428:EPHX2 protein, human; C529022:EPHX2 protein, rat