Cypchrome P450 derived Eicosanoids and target organ damage
In collaboration we investigated the role of CYP-derived epoxyeicosatrienoic acids (EETs) on maladaptive cardiac hypertrophy, electrical remodeling and sudden death. It is known that arrhythmias in patients with cardiac hypertrophy are associated with an increased risk for mortality. Known cardioprotective effects of CYP-derived EETs involve anti-inflammatory and anti-apoptotic mechanisms. Moreover EETs regulate Ca2+- and K+-channels, suggesting that increased EET biosynthesis may protect against maladaptive hypertrophy and arrhythmias. To test this hypothesis, we used male transgenic mice with cardiomyocyte-specific overexpression of the human epoxygenase CYP2J2 and analyzed the inducibility of arrhythmias in models of cardiac hypertrophy. Our results show that increased EET biosynthesis provides a strong ventricular and atrial anti-arrhythmic effect and suggest a regulatory role of EETs on ion channels and gap junction integrity as the underlying anti-arrhythmic mechanisms. In vitro studies support an involvement of a so far unknown Gi-coupled receptor that is currently under investigation.
We have taken this concept also into humans. At the ECRC we are currently conducting a fish oil study in human volunteers to analyze their influence on the CYP-derived eicosanoid pattern. We have also performed a detailed structure analysis for the anti-arrhythmic potency of CYP-derived eicosanoids leading a patent, which is the basis for the foundation of a company for the development of new drugs for atrial fibrillations. Beside the role of eicosanoids on cardiac events, we are also investigating their role in the pathogenesis of preeclampsia.