| Soluble epoxide hydrolase is a susceptibility factor for heart failure in a rat model of human disease. | |
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MedLine Citation:
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PMID: 18443590 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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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Authors:
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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 Rohde; Rainer Dietz; Stuart A Cook; Wolf-Hagen Schunck; Friedrich C Luft; Norbert Hubner |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Nature genetics Volume: 40 ISSN: 1546-1718 ISO Abbreviation: Nat. Genet. Publication Date: 2008 May |
Date Detail:
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Created Date: 2008-05-02 Completed Date: 2008-05-22 Revised Date: 2012-07-04 |
Medline Journal Info:
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Nlm Unique ID: 9216904 Medline TA: Nat Genet Country: United States |
Other Details:
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Languages: eng Pagination: 529-37 Citation Subset: IM |
Affiliation:
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Max-Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Chromosome Mapping Disease Models, Animal* Epoxide Hydrolases / analysis, genetics*, metabolism Gene Expression Profiling Genetic Linkage Genetic Predisposition to Disease* Heart Failure / enzymology, genetics*, physiopathology Humans Hypertension / complications, genetics Mice Mice, Knockout Myocardium / enzymology Polymorphism, Genetic Polymorphism, Single Nucleotide Promoter Regions, Genetic Quantitative Trait Loci Rats / genetics* Rats, Mutant Strains Sequence Analysis, DNA Sequence Deletion Transcription Factor AP-1 / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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R37 ES02710/ES/NIEHS NIH HHS; //British Heart Foundation; //Department of Health |
| Chemical | |
Reg. No./Substance:
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0/Transcription Factor AP-1; EC 3.3.2.-/Epoxide Hydrolases; EC 3.3.2.10/EPHX2 protein, human; EC 3.3.2.10/EPHX2 protein, rat |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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