Research Report 2010 - MDC

arrhythmia and sudden cardiac death. Dietary EPA/DHAsupplementation shifted the cardiac CYP-eicosanoidprofile in rats from AA- to EPA- and DHA-derivedmetabolites. One of these novel metabolites (17,18-epoxyeicosatetraenoic acid; 17,18-EETeTr) exerted a negativechronotropic effect, reduced the ß-adrenergicresponse and protected against Ca 2+ -overload in neonatalrat cardiomyocytes (in collaboration with GerdWallukat). 17,18-EETeTr was effective with an EC 50 of 1-2nM. We concluded that this metabolite may mediatethe antiarrhythmic effect of omega-3 fatty acids. Wethen identified the 11,12-double bond and the17(R),18(S)-epoxy group as the structural elementsessential for the biological activity of 17,18-EETeTr (incollaboration with John R. Falck, UT Southwestern,Dallas). Moreover, we have developed and patented syntheticagonists with improved chemical and biologicalstabilities as a basis for novel antiarrhythmic drugs.Role of catechol-o-methyltransferase (COMT) and20-HETE in acute kidney injuryAcute kidney injury (AKI) is a severe problem in variousclinical settings ranging from renal transplantation tocardiac surgery. Collaborating with Duska Dragun(Charité, Berlin), we found that carriers of the low activityCOMT allele are at significantly higher risk to developAKI after cardiac surgery. In a recent joint study, wetested the hypothesis that overproduction of 20-HETEduring ischemia/reperfusion (I/R) contributes to AKIusing an experimental rat model. We found that compoundsthat inhibit 20-HETE synthesis or 20-HETEaction significantly protected against I/R-induced vascularinflammation, tubular injury and loss of renalfunction (compare figure). These findings may offernovel therapeutic opportunities for preventing AKI andpreserving kidney function during transplantation.Selected publicationsBähring, S, Kann, M, Neuenfeld, Y, Gong, M, Chitayat, D, Toka, HR, Toka, O,Plessis, G, Maass, P, Rauch, A, Aydin, A, Luft, FC (2008) Inversion region forhypertension and brachydactyly on chromosome 12p features multiplesplicing and noncoding RNA. Hypertension. 51, 426-431.da Costa-Goncalves, AC, Tank, J, Plehm, R, Diedrich, A, Todiras, M, Gollasch,M, Heuser,, A, Wellner, M, Bader, M, Jordan, J, Luft, FC, Gross, V. (2008) Roleof the multidomain protein spinophilin in blood pressure and cardiacfunction regulation. Hypertension. 52, 702-707.Park, JK, Theuer, S, Kirsch, T, Lindschau, C, Klinge, U, Heuser, A, Plehm, R,Todiras, M, Carmeliet, P, Haller, H, Luft, FC, Muller, DN, Fiebeler, A. (2009)Growth Arrest Specific Protein 6 Participates in DOCA-Induced Target-Organ Damage. Hypertension. 54, 359-364.Monti, J, Fischer, J, Paskas, S, Heinig, M, Schulz, H, Gösele, C, Heuser, A,Fischer, R, Schmidt, C, Schirdewan, A, Gross, V, Hummel, O, Maatz, H,Patone, G, Saar, K, Vingron, M, Weldon, SM, Lindpaintner, K, Hammock, BD,Rohde, K, Dietz, R, Cook, SA, Schunck, WH, Luft, FC, Hubner, N. (2008)Soluble epoxide hydrolase is a susceptibility factor for heart failure in arat model of human disease. Nat Genet. 40, 529-537.Machnik, A, Neuhofer, W, Jantsch, J, Dahlmann, A, Tammela, T, Machura, K,Park, JK, Beck, FX, Müller DN, Derer, W, Goss, J, Ziomber, A, Dietsch, P,Wagner, H, van Rooijen, N, Kurtz, A, Hilgers, KF, Alitalo, K, Eckardt, KU, Luft,FC, Kerjaschki, D, (2009) Titze J. Macrophages regulate salt-dependentvolume and blood pressure by a vascular endothelial growth factor-Cdependentbuffering mechanism. Nat Med. 5, 545-552.Collaborations Jens TitzeOur group has collaborated closely with Jens Titze(University of Erlangen) for the past half-decade. Wedetermined that salt has a non-osmotic storage compartmentand that salt elucidates signals regardingangiogenesis (lymph vessels). The findings imply theimportance of an osmosensitive transcription factor(TonEBP) and suggest mechanisms to test the saltresistantor salt-sensitive hypertension hypothesis. Wewill rely on sodium-directed magnetic resonance imagingand spectroscopy to test our findings in humans.Cardiovascular and Metabolic Disease Research 35