Soluble epoxide hydrolase is a susceptibility factor for heart failure in a rat model of human disease
Soluble epoxide hydrolase is a susceptibility factor for heart failure in a rat model of human disease
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DOI：
10.1038/ng.129
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发表时间：
2008-05-01
期刊：
影响因子：
30.8
通讯作者：
Hubner, Norbert
中科院分区：
文献类型：
--
作者：
Monti, Jan;Fischer, Judith;Hubner, Norbert
我们的目的是通过使用人类疾病的大鼠模型来识别与心力衰竭相关的遗传变异。我们在自发性高血压心力衰竭（SHHF）大鼠和参考品系之间的F-2交叉中进行了有创心脏血流动力学测量。我们将连锁分析与全基因组表达谱分析相结合，并将Ephx 2鉴定为SHHF大鼠的心力衰竭易感基因。具体地说，我们发现Ephx 2的顺式变异与心力衰竭分离，并增加转录表达，蛋白质表达和酶活性，导致心脏保护性环氧二十碳三烯酸更快的水解。为了证实我们的结果，我们使用敲除小鼠测试了Ephx 2在心力衰竭中的作用。Ephx 2基因消融可防止压力超负荷诱导的心力衰竭和心律失常我们进一步证明了EPHX 2在人类心力衰竭中的差异调节，表明Ephx 2在这种复杂疾病中具有跨物种作用。
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 F-2 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.