| Literature DB >> 18443590 |
Jan Monti1, 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 Rohde, Rainer Dietz, Stuart A Cook, Wolf-Hagen Schunck, Friedrich C Luft, Norbert Hubner.
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.Entities:
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Year: 2008 PMID： 18443590 PMCID： PMC7370537 DOI： 10.1038/ng.129
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330