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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.

SUBMITTER: Monti J

PROVIDER: S-EPMC7370537 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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

Monti Jan J Fischer Judith J Paskas Svetlana S Heinig Matthias M Schulz Herbert H Gösele Claudia C Heuser Arnd A Fischer Robert R Schmidt Cosima C Schirdewan Alexander A Gross Volkmar V Hummel Oliver O Maatz Henrike H Patone Giannino G Saar Kathrin K Vingron Martin M Weldon Steven M SM Lindpaintner Klaus K Hammock Bruce D BD Rohde Klaus K Dietz Rainer R Cook Stuart A SA Schunck Wolf-Hagen WH Luft Friedrich C FC Hubner Norbert N

Nature genetics 20080501 5

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 incre ...[more]

PMID: 18443590

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Project description:Background Single nucleotide polymorphisms (SNPs) in the EPHX2 gene have been implicated in susceptibility to cardiovascular diseases, including coronary heart disease (CHD). EPHX2 encodes for soluble epoxide hydrolase, an important enzyme involved in the metabolic breakdown of arachidonic acid-derived vasoactive and anti-inflammatory eicosanoids referred to as epoxyeicosatrienoic acids to their corresponding diols. Our pilot study aimed to investigate whether common SNPs such as rs751141, rs4149253, and rs1042064 of the EPHX2 gene are associated with susceptibility to CHD in Russian population. Methods A total of 1,183 unrelated Russian subjects comprising 602 patients with angiographically diagnosed CHD and 581 age- and sex-matched healthy subjects were recruited and their DNA samples were genotyped for the selected SNPs using a high-throughput Mass-ARRAY genotyping platform. Results No significant associations were found between the investigated SNPs and CHD risk (P>0.05). A polymorphism rs751141 (amino acid substitution, R287Q) displayed a trend towards association with CHD (odds ratio adjusted by sex and age was 3.02, 95% CI: 0.97–9.43, P correction =0.16). SNP-smoking interaction analyses did not identify synergic effects of the studied SNPs and cigarette smoking on the disease risk (P>0.05). A linkage disequilibrium was found between SNPs rs751141 and rs4149253 (D’ =0.995), rs751141 and rs1042064 (D’ =0.967), rs4149253 and rs1042064 (D’ =0.965). Four common haplotypes G-G-T (73%), A-G-C (10%), G-G-C (9%) and G-A-C (7%) have been identified, however, none of them showed a significant association with the risk of CHD in the studied population (P>0.05). Conclusions The investigated polymorphisms do not contribute to CHD susceptibility in our population. Nevertheless, because of a limited number of SNPs was investigated in this study, definitive conclusions yet to be made in further studies on the contribution of the EPHX2 gene to the development of CHD in Russians.

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

Publications

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

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