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

• Antragsteller: Dr. Wolf-Hagen Schunck
• Fachliche Zuordnung: Nephrologie
• Förderung: Förderung von 2008 bis 2016
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 60843499

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.

• DFG-Verfahren: Forschungsgruppen
• Teilprojekt zu: FOR 1054: Sex-specific mechanisms in myocardial hypertrophy
• Beteiligte Personen: Dr. Robert Fischer; Professor Dr. Dominik N. Müller