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

Max-Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
Nature Genetics (Impact Factor: 29.65). 06/2008; 40(5):529-37. DOI: 10.1038/ng.129
Source: PubMed

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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Epigenetic marks such as cytosine methylation are important determinants of cellular and whole-body phenotypes. However, the extent of, and reasons for inter-individual differences in cytosine methylation, and their association with phenotypic variation are poorly characterised. Here we present the first genome-wide study of cytosine methylation at single-nucleotide resolution in an animal model of human disease. We used whole-genome bisulfite sequencing in the spontaneously hypertensive rat (SHR), a model of cardiovascular disease, and the Brown Norway (BN) control strain, to define the genetic architecture of cytosine methylation in the mammalian heart and to test for association between methylation and pathophysiological phenotypes. Analysis of 10.6 million CpG dinucleotides identified 77,088 CpGs that were differentially methylated between the strains. In F1 hybrids we found 38,152 CpGs showing allele-specific methylation and 145 regions with parent-of-origin effects on methylation. Cis-linkage explained almost 60% of inter-strain variation in methylation at a subset of loci tested for linkage in a panel of recombinant inbred (RI) strains. Methylation analysis in isolated cardiomyocytes showed that in the majority of cases methylation differences in cardiomyocytes and non-cardiomyocytes were strain-dependent, confirming a strong genetic component for cytosine methylation. We observed preferential nucleotide usage associated with increased and decreased methylation that is remarkably conserved across species, suggesting a common mechanism for germline control of inter-individual variation in CpG methylation. In the RI strain panel, we found significant correlation of CpG methylation and levels of serum chromogranin B (CgB), a proposed biomarker of heart failure, which is evidence for a link between germline DNA sequence variation, CpG methylation differences and pathophysiological phenotypes in the SHR strain. Together, these results will stimulate further investigation of the molecular basis of locally regulated variation in CpG methylation and provide a starting point for understanding the relationship between the genetic control of CpG methylation and disease phenotypes.
    PLoS Genetics 12/2014; 10(12):e1004813. DOI:10.1371/journal.pgen.1004813 · 8.17 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Reactivation of fetal gene expression patterns has been implicated in common cardiac dis-eases in adult life including left ventricular (LV) hypertrophy (LVH) in arterial hypertension. Thus, increased wall stress and neurohumoral activation are discussed to induce the return to expression of fetal genes after birth in LVH. We therefore aimed to identify novel potential candidates for LVH by analyzing fetal-adult cardiac gene expression in a genetic rat model of hypertension, i.e. the stroke-prone spontaneously hypertensive rat (SHRSP). To this end we performed genome-wide transcriptome analysis in SHRSP to identify differences in ex-pression patterns between day 20 of fetal development (E20) and adult animals in week 14 in comparison to a normotensive rat strain with contrasting low LV mass, i.e. Fischer (F344). 15232 probes were detected as expressed in LV tissue obtained from rats at E20 and week 14 (p < 0.05) and subsequently screened for differential expression. We identified 24 genes with SHRSP specific up-regulation and 21 genes with down-regulation as com-pared to F344. Further bioinformatic analysis presented Efcab6 as a new candidate for LVH that showed only in the hypertensive SHRSP rat differential expression during development (logFC = 2.41, p < 0.001) and was significantly higher expressed in adult SHRSP rats com-pared with adult F344 (+ 76%) and adult normotensive Wistar-Kyoto rats (+ 82%). Thus, it represents an interesting new target for further functional analyses and the elucidation of mechanisms leading to LVH. Here we report a new approach to identify candidate genes for cardiac hypertrophy by combining the analysis of gene expression differences between strains with a contrasting cardiac phenotype with a comparison of fetal-adult cardiac expres-sion patterns.
    PLoS ONE 03/2015; 10(2). DOI:10.1371/journal.pone.0116807 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Heart failure accounts for a significant portion of heart diseases. Molecular mechanisms gradually emerge that participate in pathways leading to left ventricular dysfunction in common systolic heart failure (SHF) and diastolic heart failure (DHF). A human genome-wide association study (GWAS) identified two markers for SHF and no GWAS on DHF has been documented. However, genetic analyses in rat models of SHF and DHF have begun to unravel the genetic components known as quantitative trait loci (QTLs) initiating systolic and diastolic function. A QTL for systolic function was detected and the gene responsible for it is identified to be that encoding the soluble epoxide hydrolase. Diastolic function is determined by multiple QTLs and the Ccl2/monocyte chemotactic protein gene is the strongest candidate. An amelioration on diastolic dysfunction is merely transient from changing such a single QTL accompanied by a blood pressure reduction. A long-term protection can be achieved only via combining alleles of several QTLs. Thus, distinct genes in synergy are involved in physiological mechanisms durably ameliorating or reversing diastolic dysfunction. These data lay the foundation for identifying causal genes responsible for individual diastolic function QTLs and the essential combination of them to attain a permanent protection against diastolic dysfunction, and consequently will facilitate the elucidation of pathophysiological mechanisms underlying hypertensive diastolic dysfunction. Novel pathways triggering systolic and diastolic dysfunction have emerged that will likely provide new diagnostic tools, innovative therapeutic targets and strategies in reducing, curing and even reversing SHF and DHF.
    Journal of Hypertension 11/2014; 33(1). DOI:10.1097/HJH.0000000000000400 · 4.22 Impact Factor

Full-text (2 Sources)

Available from
May 27, 2014