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: 29.35). 06/2008; 40(5):529-37. DOI: 10.1038/ng.129
Source: PubMed


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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    • "Protective role of sEHIs sEH enzyme is an important enzyme that is highly expressed during CH and has been implicated in the development of several CVDs (Imig et al., 2002; Imig, 2005; Kaur & Gill, 1985; Monti et al., 2008; Sinal et al., 2000). This implication arises because of the metabolic conversion of fatty acid epoxides, such as EETs, to the biologically less active metabolite DHETs, which diminishes the beneficial effects of EETs on heart function. "
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    ABSTRACT: Abstract A plethora of studies have demonstrated the expression of cytochrome P450 (CYP) and soluble epoxide hydrolase (sEH) enzymes in the heart and other cardiovascular tissues. In addition, the expression of these enzymes is altered during several cardiovascular diseases (CVDs), including cardiac hypertrophy (CH). The alteration in CYP and sEH expression results in derailed CYP-mediated arachidonic acid (AA) metabolism. In animal models of CH, it has been reported that there is an increase in 20-hydroxyeicosatetraenoic acid (20-HETE) and a decrease in epoxyeicosatrienoic acids (EETs). Further, inhibiting 20-HETE production by CYP ω-hydroxylase inhibitors and increasing EET stability by sEH inhibitors have been proven to protect against CH as well as other CVDs. Therefore, CYP-mediated AA metabolites 20-HETE and EETs are potential key players in the pathogenesis of CH. Some studies have investigated the molecular mechanisms by which these metabolites mediate their effects on cardiomyocytes and vasculature leading to pathological CH. Activation of several intracellular signaling cascades, such as nuclear factor of activated T cells, nuclear factor kappa B, mitogen-activated protein kinases, Rho-kinases, Gp130/signal transducer and activator of transcription, extracellular matrix degradation, apoptotic cascades, inflammatory cytokines, and oxidative stress, has been linked to the pathogenesis of CH. In this review, we discuss how 20-HETE and EETs can affect these signaling pathways to result in, or protect from, CH, respectively. However, further understanding of these metabolites and their effects on intracellular cascades will be required to assess their potential translation to therapeutic approaches for the prevention and/or treatment of CH and heart failure.
    Full-text · Article · May 2013 · Drug Metabolism Reviews
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    • "The inverse correlation between sEH expression and activity on one side and cardiac hypertrophy and heart failure on the other side has been previously reported (Monti et al. 2008; Xu et al. 2006; Ai et al. 2009). With regard to hypertrophy, it has been previously reported that the administration of sEH inhibitors protect against angiotensin II-induced hypertrophy in male Wistar rats and reversed chronic pressure overloadinduced cardiac hypertrophy through thoracic aortic constriction in C57Bl/6 mice, as demonstrated by the decreased left-ventricular hypertrophy, reduced cardiomyocyte size hypertrophic markers expression, including atrial natriuretic factor and β-myosin heavy chain (Ai et al. 2009; Xu et al. 2006). "
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    ABSTRACT: Acute arsenic (As(III)) exposure has been reported to cause cardiac toxicity, however this toxicity was never linked to the disturbance in cytochrome P450 (P450)-mediated arachidonic acid metabolism. Therefore, we investigated the effect of acute As(III) toxicity on the expression of P450 and soluble epoxide hydrolase (sEH) and their associated arachidonic acid metabolism in mice hearts. As(III) toxicity was induced by a single intraperitoneal injection of 12.5 mg/kg of As(III). Our results showed that As(III) treatment caused a significant induction of the cardiac hypertrophic markers in addition to Cyp1b1, Cyp2b, Cyp2c, Cyp4f, and sEH gene expression in mice hearts. Furthermore, As(III) increased sEH protein expression and activity in hearts with a consequent decrease in 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) formation. Whereas the formation of 8,9-, 11,12-, 14,15-dihydroxyeicosatrienoic acids (DHETs) was significantly increased. As(III) also increased sEH mRNA and protein expression levels in addition to the hypertrophic markers which was reversed by knockdown of sEH in H9c2 cells. In conclusion, acute As(III) toxicity alters the expression of several P450s and sEH enzymes with a consequent decrease in the cardioprotective EETs which may represent a novel mechanism by which As(III) causes progressive cardiotoxicity. Furthermore, inhibiting sEH might represent a novel therapeutic approach to prevent As(III)-induced hypertrophy.
    Full-text · Article · Jun 2012 · Xenobiotica
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    • "Ephx2(Ϫ/Ϫ) mice were used as one model of increased EET levels. Genetic disruption of sEH activity has previously been used to explore the role of EETs in blood pressure, cardioprotection , systemic inflammation, heart failure, diabetes, and vascular remodeling (Seubert et al., 2006; Luria et al., 2007; Monti et al., 2008; Luo et al., 2010; Simpkins et al., 2010). A series of potent and selective inhibitors of sEH have also been synthesized, and several have been tested in animal and cellular models (Yu et al., 2000b; Davis et al., 2002; Imig et al., 2002, 2005; Zhao et al., 2004; Schmelzer et al., 2005; Smith et al., 2005; Luria et al., 2007). "
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    ABSTRACT: Acute kidney injury is associated with a significant inflammatory response that has been the target of renoprotection strategies. Epoxyeicosatrienoic acids (EETs) are anti-inflammatory cytochrome P450-derived eicosanoids that are abundantly produced in the kidney and metabolized by soluble epoxide hydrolase (sEH; Ephx2) to less active dihydroxyeicosatrienoic acids. Genetic disruption of Ephx2 and chemical inhibition of sEH were used to test whether the anti-inflammatory effects of EETs, and other lipid epoxide substrates of sEH, afford protection against cisplatin-induced nephrotoxicity. EET hydrolysis was significantly reduced in Ephx2(-/-) mice and was associated with an attenuation of cisplatin-induced increases in serum urea nitrogen and creatinine levels. Histological evidence of renal tubular damage and neutrophil infiltration was also reduced in the Ephx2(-/-) mice. Likewise, cisplatin had no effect on renal function, neutrophil infiltration, or tubular structure and integrity in mice treated with the potent sEH inhibitor 1-adamantan-1-yl-3-(1-methylsulfonyl-piperidin-4-yl-urea) (AR9273). Consistent with the ability of EETs to interfere with nuclear factor-κB (NF-κB) signaling, the observed renoprotection was associated with attenuation of renal NF-κB activity and corresponding decreases in the expression of tumor necrosis factor (TNF) α, TNF receptor (TNFR) 1, TNFR2, and intercellular adhesive molecule-1 before the detection of tubular injury. These data suggest that EETs or other fatty acid epoxides can attenuate cisplatin-induced kidney injury and sEH inhibition is a novel renoprotective strategy.
    Preview · Article · Mar 2012 · Journal of Pharmacology and Experimental Therapeutics
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