Die Bedeutung der "PKC-dependent Protein-Phosphatase 1 Inhibitor" (KEPI) für die Entwicklung und Funktion des Herzens.
Zusammenfassung der Projektergebnisse
Cardiac muscle function is regulated by a tight balance between phosphorylation and dephosphorylation of different regulatory phosphoproteins like phospholamban, the ryanodine receptor, L-type Ca2+ channel and troponin I. The role of protein kinases in cardiac contractility has been well characterized, whereas the importance of phosphatases and their regulatory proteins is poorly understood. This study focuses on the cardiac function of KEPI (Protein Kinase C enhanced protein phosphatase type 1 inhibitor), which is a recently identified protein with inhibitory properties on the crucial cardiac phosphatase called PP1 (Protein Phosphatase 1). We characterized the embryonic expression of KEPI in heart and found the mRNA expressed at day 8.5 pf in the cardiac outflow tract. At day 10.5 the expression was extended to ventricles and finally at day 14 to the whole heart. This expression pattern indicates KEPI´s possible involvement in cardiac development. To examine KEPI´s functional significance in adult heart, we generated a KEPI transgenic mouse with cardiomycyte specific overexpression. Echocardiography revealed that KEPI overexpressing mice developed age-dependent cardiac hypercontractility, which progressed since the age of 20 weeks on. The phenotype was associated with enhanced contractile performance on single cell level observed already at the age of 12 weeks. Further, we found in transgenic vs. wild type cardiomyocytes an enhanced and accelerated Ca2+-transient as assessed by Fura-2 measurement. Interestingly, KEPI overexpressing hearts display higher sensitivity to acute ß-adrenergic stimulation as assayed in a Langendorff-model. Accordingly, KEPI transgenic hearts responded to a chronic stimulation with Isoproterenol with enhanced contractility. However, this fact was not related to increased hypertrophy (30mg/kg/d for 7 days). Taken together, this study reveals KEPI as a new regulator of cardiac contractility. Moreover, the improved cardiac performance and Ca2+-transient in transgenic cardiomyocytes suggest KEPI´s participation in the regulation of Contraction-Excitation-Coupling and modulation of the ß-adrenergic response.
Projektbezogene Publikationen (Auswahl)
- A missense variant in desmoglein-2 predisposes to dilated cardiomyopathy; Mol Genet Metab. 2008 Sep-Oct;95(1- 2):74-80
Posch MG, Posch MJ, Geier C, Erdmann B, Mueller W, Richter A, Ruppert V, Pankuweit S, Maisch B, Perrot A, Buttgereit J, Dietz R, Haverkamp W, Ozcelik C
- Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy; Hum Mol Genet. 2008 Sep 15;17(18):2753- 65
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, Nägele H, Scheffold T, Dietz R, Chien KR, Spuler S, Fürst DO, Nürnberg P, Ozcelik C
- Connective tissue growth factor overexpression in cardiomyocytes promotes cardiac hypertrophy and protection against pressure overload; PLoS One. 2009 Aug 25;4(8):e6743. Erratum in: PLoS One. 2009;4(9)
Panek AN, Posch MG, Alenina N, Ghadge SK, Erdmann B, Popova E, Perrot A, Geier C, Dietz R, Morano I, Bader M, Ozcelik C
- Identification of mutational hot spots in LMNA encoding lamin A/C in patients with familial dilated cardiomyopathy; Basic Res Cardiol. 2009 Jan;104(1):90-9
Perrot A, Hussein S, Ruppert V, Schmidt HH, Wehnert MS, Duong NT, Posch MG, Panek A, Dietz R, Kindermann I, Böhm M, Michalewska-Wludarczyk A, Richter A, Maisch B, Pankuweit S, Ozcelik C
- A gain-of-function TBX20 mutation causes congenital atrial septal defects, patent foramen ovale and cardiac valve defects; J Med Genet. 2010 Apr;47(4):230-5
Posch MG, Gramlich M, Sunde M, Schmitt KR, Lee SH, Richter S, Kersten A, Perrot A, Panek AN, Al Khatib IH, Nemer G, Mégarbané A, Dietz R, Stiller B, Berger F, Harvey RP, Ozcelik C
- A myomesin mutation associated with hypertrophic cardiomyopathy deteriorates dimerisation properties.;Biochem Biophys Res Commun. 2011 Feb 18; 405(3):473-9
Siegert R, Perrot A, Keller S, Behlke J, Michalewska-Włudarczyk A, Wycisk A, Tendera M, Morano I, Ozcelik C
- Right ventricular myocardial systolic and diastolic dysfunction in heart failure with normal left ventricular ejection fraction.; J Am Soc Echocardiogr. 2011 Aug;24(8):886-97
Morris DA, Gailani M, Vaz Pérez A, Blaschke F, Dietz R, Haverkamp W, Özcelik C
