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

细胞色素 P450 依赖性类二十烷酸在心脏肥大和心律失常的性别特异性机制中的作用

• 批准号: 79541554
• 负责人: Dr. Wolf-Hagen Schunck
• 金额: --
• 依托单位: Max-Delbrück-Centrum für Molekulare Medizin (MDC) in der Helmholtz-Gemeinschaft
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/79541554?language=en
• 关键词: Cytochrome; P450; dependent; eicosanoids; sex

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.

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，我们的结果揭示了女性和CYP-环氧二十烷酸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。