Research Report 2010 - MDC

the prevention and treatment. The subgroup of FlorianBlaschke is elucidating the role of those nuclear receptorsin cardiac metabolism and hypertrophy both invitro and in vivo and characterize the molecular mechanismsutilized to regulate gene expression involved incardiomyocyte growth and energy metabolism.Apoptosis and Regeneration in Heart FailureStefan Donath, Junfeng AnAnother focus of the group has addressed the issue ofapoptosis in heart failure progression. ARC (apoptosisrepressor with caspase recruitment domain) is a masterregulator of cardiac death signaling, as it is the onlyknown factor that specifically inhibits both deathreceptor and mitochondrial apoptotic death pathways.By generating ARC deficient mice the subgroup ofStefan Donath attempted to elucidate the physiologicalrole of ARC in the heart. Upon biomechanical stressinduced by aortic banding, ARC null mice developedaccelerated cardiomyopathy compared with littermatecontrols that was characterized by reduced contractilefunction, cardiac enlargement, and myocardial fibrosis.Likewise, ischemia-reperfusion injury of ARC null miceresulted in markedly increased myocardial infarct sizes.The pathophysiological relevance was underscored byspecimens from failing human hearts showing markedlyreduced ARC protein levels. Thus, they identified a tissue-specificanti-apoptotic factor which is downregulatedin human failing myocardium and which isrequired for cardioprotection in pressure overload andischemia. Inhibition of apoptosis might have a similareffect on restoration of the balance between loss of cardiomyocytesand heart renewal by strengthening theself-renewal properties of the heart.Transcription Factors in Myocardial StressRemodellingLaura Zelarayán, Martin Bergmann (guest scientist),Maria-Patapia ZafiriouThe subgroup of Laura Zelarayán and Martin Bergmannelucidated the role of the Wnt/β-catenin pathway inactivation of endogenous cardiac progenitor cells.Therefore, they deleted the β-catenin gene in themyocardium by using the Cre/loxP technology. The conditionalknockout of β-catenin resulted in cardiachypertrophy, suggesting that β-catenin downregulationmight be part of the adaptive cardiac hypertrophyresponse. Additionally, the depletion of β-catenin positivelyaffected LV-function and survival after experimentalmyocardial infarction (figure 1). Furthermore,conditional β-catenin deficient mice displayed betterremodelling upon cardiac stress. Isolated Sca-1 pos cellsfrom mutant mice showed significantly increased differentiationcapacity.Pathological Cardiac Remodelling in Heart FailureJens FielitzA further gene family that suppresses stress-dependentremodelling of the heart via association with the MEF2transcription factor are class II histone deacetylases(HDACs). Protein kinase D (PKD) is a stress-responsivekinase that phosphorylates class II HDACs, resulting intheir dissociation from MEF2 with consequent activationof MEF2 target genes. The subgroup of Jens Fielitzwas able to show that the cardiac ablation of PKD1showed less hypertrophy and a dramatic reduction incardiac fibrosis compared to wild type mice when subjectedto aortic banding (figure 2). In addition, PKD1mutant mice were resistant to left ventricular dilatationand a decrease in contractility. This study indicatesthat PKD1 functions as a key transducer of stress stimuliinvolved in pathological cardiac remodelling in vivo.These findings provide the first evidence that deletionof a class II HDAC kinase in vivo diminishes stressinducedhypertrophy.Selected PublicationsAn, J, Li, P, Li, J, Dietz, R, Donath, S. (2009). ARC is a critical cardiomyocytesurvival switch in doxorubicin cardiotoxicity. J Mol Med. 87, 401-10.Fielitz, J, Kim, MS, Shelton, JM, Qi, X, Hill, JA, Richardson, JA, Bassel-Duby, R,Olson, EN. (2008). Requirement of protein kinase D1 for pathologicalcardiac remodeling. Proc Natl Acad Sci U S A. 105, 3059-3063.Geier, C, Gehmlich, K, Ehler, E, Hassfeld, S, Perrot, A, Hayess, K, Cardim, N,Wenzel, K, Erdmann, B, Krackhardt, F, Posch, MG, Osterziel, KJ, Bublak, A,Nagele, H, Scheffold, T, Dietz, R, Chien, KR, Spuler, S, Furst, DO, Nurnberg, P,Ozcelik, C. (2008). Beyond the sarcomere: CSRP3 mutations causehypertrophic cardiomyopathy. Hum Mol Genet. 17, 2753-2765.Monti, J, Fischer, J, Paskas, S, Heinig, M, Schulz, H, Gosele, 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.Wenzel, K, Haase, H, Wallukat, G, Derer, W, Bartel, S, Homuth, V, Herse, F,Hubner, N, Schulz, H, Janczikowski, M, Lindschau, C, Schroeder, C,Verlohren, S, Morano, I, Muller, DN, Luft, FC, Dietz, R, Dechend, R,Karczewski, P. (2008). Potential relevance of alpha(1)-adrenergic receptorautoantibodies in refractory hypertension. PLoS One. 3, e3742.Zelarayán, LC, Noack, C, Sekkali, B, Kmecova, J, Gehrke, C, Renger, A, Zafiriou,MP, van der Nagel, R, Dietz, R, de Windt, LJ, Balligand, JL, Bergmann, MW.(2008). Beta-Catenin downregulation attenuates ischemic cardiacremodeling through enhanced resident precursor cell differentiation.Proc Natl Acad Sci U S A. 105, 19762-19767.Cardiovascular and Metabolic Disease Research 41