Cytochrome P450-dependent eicosanoids in sex-specific mechanisms of cardiac hypertrophy and arrhythmia

在第一个资助期，我们发现CYP-类花生酸以性别特异性方式干扰适应不良性心脏肥大的发展。特别是，我们的研究结果揭示了女性性别和CYP-epoxyeicosanoids在肥大诱导的心律失常易感性和死亡率中的保护作用。基于这些发现，我们现在假设雌二醇和CYP-epoxyeicosanoids可能有助于通过协同和部分会聚途径调节心肌细胞的电兴奋性，线粒体功能和细胞-细胞偶联。我们将使用已建立的适应不良心脏肥大小鼠模型，并将继续分析性别和CYP-类花生酸对心律失常诱导、间隙连接完整性和“心律决定因子”（HRD）基因网络的影响。用离体心脏补充研究将有助于剖析电重构的重要特征，如传导速度、动作电位形状和持续时间以及钙循环的变化。此外，我们将使用培养的心肌细胞，以确定由雌二醇和CYP-epoxyeicosanoids，以及相应的信号通路的相互作用位点触发的抗心律失常机制。

In the first funding period, we found that CYP-eicosanoids interfere with the development of maladaptive cardiac hypertrophy in a sex-specific manner. In particular, our results revealed a protective role of female sex and CYP-epoxyeicosanoids in hypertrophy-induced arrhythmia susceptibility and mortality. Based on these findings, we now hypothesize that estradiol and CYP-epoxyeicosanoids may contribute via synergistic and partially converging pathways to the regulation of electric excitability, mitochondrial function, and cell-cell coupling in cardiomyocytes. We will use established mouse models of maladaptive cardiac hypertrophy and will continue to analyze the impact of sex and CYP-eicosanoids on arrhythmia inducibility, gap junction integrity, and the “heart-rhythm-determinant” (HRD) gene network. Complementing studies with isolated hearts will serve to dissect important features of electrical remodeling such as changes in conduction velocities, action potential shape and-duration, and calcium cycling. Moreover, we will use cultured cardiomyocytes to identify the anti-arrhythmic mechanisms triggered by estradiol and CYP-epoxyeicosanoids, as well as the interaction sites of the corresponding signaling pathways.