Journal Article

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

Dietz, Rainer, Luft, Friedrich C, Gross, Volkmar, Rohde, Klaus, Fischer, Robert, Patone, Giannino, Paskas, Svetlana, Fischer, Judith, Heinig, Matthias, Schulz, Herbert, Hammock, Bruce D, Cook, Stuart A, Vingron, Martin, Schmidt, Cosima, Saar, Kathrin, Schunck, Wolf-Hagen, Maatz, Henrike, Lindpaintner, Klaus, Schirdewan, Alexander, Hubner, Norbert, Hummel, Oliver, Gösele, Claudia, Weldon, Steven M, Heuser, Arnd, Monti, Jan

2008

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Agriculture / Animal Genetics and Genomics / Animals / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cardiovascular disease / Chromosome Mapping / Disease Models, Animal / Enzymatic activity / Epoxide Hydrolases - analysis / Epoxide Hydrolases - genetics / Epoxide Hydrolases - metabolism / Gene Expression Profiling / Gene Function / Genetic aspects / Genetic Linkage / Genetic Predisposition to Disease / Genetic variance / Genetic variation / Genetics / Genotype & phenotype / Health aspects / Heart failure / Heart Failure - enzymology / Heart Failure - genetics / Heart Failure - physiopathology / Heart surgery / Hemodynamics / Human Genetics / Humans / Hypertension - complications / Hypertension - genetics / Mice / Mice, Knockout / Myocardium - enzymology / Polymorphism, Genetic / Polymorphism, Single Nucleotide / Principal components analysis / Promoter Regions, Genetic / Quantitative Trait Loci / Rats - genetics / Rats, Mutant Strains / Rodents / Sequence Analysis, DNA / Sequence Deletion / Transcription Factor AP-1 - metabolism