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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.

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Figure 1: Colocalization of cardiac phenotype QTL on chromosome 15.
Figure 2: Polymorphisms in Ephx2 regulatory and coding region.
Figure 3: Ephx2 expression and sEH activity in heart tissue.
Figure 4: Promoter polymorphisms of Ephx2 influence promoter activity.
Figure 5: Identification of regulatory trans eQTLs mapping to chromosome 15.
Figure 6: Characterization of Ephx2−/− mice by telemetry and echocardiography.
Figure 7: Electrophysiological characterization of Ephx2−/− and wild-type mice after Ang II treatment (n = 4 per group).
Figure 8: EPHX2 mRNA expression is downregulated in individuals with heart failure.

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Acknowledgements

We thank A. Müller, H. Kistel, A. Schiche, J. Mothes, J. Meisel, M. Rothe and M. Taube for technical assistance. We acknowledge funding to N.H. from the German Ministry for Science and Education (National Genome Research Network) and support through STAR and EURATools (European Commission contract LSHG-CT-2004-005235 and LSHG-CT-2005-019015); to F.C.L. and W.-H.S. from the Deutsche Forschungsgemeinschaft; to B.D.H. from US National Institute of Environmental Health Sciences grant R37 ES02710; and to S.A.C. from the British Heart Foundation and the UK Department of Health.

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N.H. and J.M. developed the project. N.H. directed the project. J.F., S.P., C.G., C.S., H.M., G.P., K.S., S.A.C. and W.-H.S. performed genetic and biochemical analysis. J.M., A.H., R.F., A.S., V.G., R.D. and F.C.L. performed and analyzed physiological experiments. M.H., H.S., O.H., M.V. and K.R. carried out statistical analysis. B.D.H., S.M.W., K.L. and S.A.C. contributed materials. N.H. wrote the paper with J.M., J.F. and F.C.L.

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Correspondence to Norbert Hubner.

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Monti, J., Fischer, J., Paskas, S. et al. Soluble epoxide hydrolase is a susceptibility factor for heart failure in a rat model of human disease. Nat Genet 40, 529–537 (2008). https://doi.org/10.1038/ng.129

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