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

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

Research output: Contribution to journalArticle

130 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)529-537
Number of pages9
JournalNature Genetics
Volume40
Issue number5
DOIs
StatePublished - 2008

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ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Monti, J., Fischer, J., Paskas, S., Heinig, M., Schulz, H., Gösele, C., Heuser, A., Fischer, R., Schmidt, C., Schirdewan, A., Gross, V., Hummel, O., Maatz, H., Patone, G., Saar, K., Vingron, M., Weldon, S. M., Lindpaintner, K., Hammock, B. D., ... Hubner, N. (2008). Soluble epoxide hydrolase is a susceptibility factor for heart failure in a rat model of human disease. Nature Genetics, 40(5), 529-537. https://doi.org/10.1038/ng.129