Monti Jan, Fischer Judith, Paskas Svetlana, Heinig Matthias, Schulz Herbert, Gösele Claudia, Heuser Arnd, Fischer Robert, Schmidt Cosima, Schirdewan Alexander, Gross Volkmar, Hummel Oliver, Maatz Henrike, Patone Giannino, Saar Kathrin, Vingron Martin, Weldon Steven M, Lindpaintner Klaus, Hammock Bruce D, Rohde Klaus, Dietz Rainer, Cook Stuart A, Schunck Wolf-Hagen, Luft Friedrich C, Hubner Norbert
Max-Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
Nat Genet. 2008 May;40(5):529-37. doi: 10.1038/ng.129.
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.
我们旨在通过使用人类疾病的大鼠模型来鉴定与心力衰竭相关的基因变异。我们在自发性高血压心力衰竭（SHHF）大鼠与参考品系之间的F2杂交后代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，并确定Ephx2是SHHF大鼠中的一个心力衰竭易感基因。具体而言，我们发现Ephx2的顺式变异与心力衰竭以及转录本表达增加、蛋白质表达增加和酶活性增加相关，导致具有心脏保护作用的环氧二十碳三烯酸的水解加快。为了证实我们的结果，我们使用基因敲除小鼠测试了Ephx2在心力衰竭中的作用。Ephx2基因缺失可预防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EPHX2在人类心力衰竭中的差异调节，表明Ephx2在这种复杂疾病中具有跨物种作用。
