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-二十烷类化合物以一种性别特异性的方式干扰适应性不良心肌肥厚的发展。特别是，我们的结果揭示了女性和环氧二十烷醇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-环氧二十烷类化合物可能通过协同和部分收敛的途径调节心肌细胞的电兴奋性、线粒体功能和细胞-细胞耦合。我们将使用已建立的适应性不良的心肌肥厚的小鼠模型，并将继续分析性别和CYP-二十烷基类化合物对心律失常的诱导性、缝隙连接完整性和“心率-节奏-决定因素”(HRD)基因网络的影响。对离体心的补充研究将有助于剖析电重构的重要特征，如传导速度、动作电位形状和时程的变化，以及钙循环。此外，我们将利用培养的心肌细胞来鉴定雌二醇和环氧二十烷酸类化合物触发的抗心律失常机制，以及相应的信号通路的相互作用部位。

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.