Adrenergic regulation of cardiac IK1 currents
Downregulation of inward rectifier IK1 currents is a hallmark of electrical remodeling in congestive heart failure and leads to ventricular arrhythmia. We were able to show that certain proarrhythmic catecholaminergic signalling pathways in congestive heart failure lead to an inhibition of cardiac IK1 current. A direct phosphorylation of the underlying channel subunit is the underlying mechanism. At the moment, we are working on the identification of the exact molecular mechanism in transgenic mice and conditional knock-out mice to evaluate potential new targets for antiarrhythmic therapies downstream of the cardiac adrenergic receptors.
Ca2+ homeostasis in cardiac purkinje fibres and their role in the generation of focal ventricular arrhythmia in heart failure
New approaches in the pathophysiology of focal ventricular arrhythmia have brought dysregulation of Ca2+ homeostasis and electrophysiological remodeling in the purkinje fibres into the focus of attention. Based on the differential expression profile of cardiac purkinje fibres vs. myocardium, it is possible to specifically modify purkinje fibres through transgenic techniques.
In this cooperation project (with the group of Prof. Johannes
Backs), we generate genetically modified mouse models with
specific expression and conditional knock-out in purkinje
fibres. These models will be evaluated regarding their
electrophysiological characteristics after induction of heart failure.
DFG funding for this project is planned for 2014.
Autoimmune mechanisms in the pathogenesis of idiopathic conduction disease
Pathogenesis, progression and prognosis of chronic heart failure are considerably modified by circulating autoantibodies. By presenting self-antigens to the components of the immune system following cardiac injury induced by endogenous or exogenous factors, cardiac autoimmunity may be induced in susceptible patients and cause secondary myocardial damage. Particularly, autoantibodies have been linked to heart failure. However, in a cooperation with the group of Prof. Kaya from within our departement, we recently demonstrated a causal relationship between the occurence of specific autoantibodies and conduction disease by provocating an autoimmune response to cardiac voltage-gated sodium channel Nav1.5. In immunized rats, we observed episodes of third-degree atrioventricular and sinoatrial block in every animal.
Furthermore, in patients with idiopathic atrioventricular block from our out-patient
clinic, we observed autoantibodies against Nav1.5 that were
absent in sera from healthy controls.
Based on these results, we intend to further characterize autoimmune
mechanisms in the pathogenesis of cardiac conduction disease.
DFG funding for this project is planned for 2014.
Regulation of endothelial and mycardial aquaporin-1 channels
Aquaporin-1 channels are the functionally dominant water channels in some endothelia and in cardiomyocytes. For related aquaporins, it was shown that they determine ion homeostasis and therefore can modulate the electrical properties of excitable cells. Recently, we were able to show that aquaporin-1 function is strongly regulated by protein kinase C and that this regulation is of functional importance in native cells. Therefore we generated a floxed aquaporin-1 knock-out mouse to conduct detailed pathophysiological studies. At the moment, we are crossing these mice to generate conditional knock-outs in specific endothelial and in myocardial cells. These models will be characterized in experimental peritoneal dialysis models and in a sepsis model (endothelial knock-out) and through cardiac and electrophysiological phenotyping (myocardial knock-out).
This project is performed in cooperation with Prof. Schwenger (Nephrology, Heidelberg) and is funded by the DFG.
Research Techniques/Scientific Methods
Cellular and molecular electrophysiology, biochemistry, high-resolution imaging (in cooperation with the Kirchhoff-Institut für Physik), transgenic animal models.
Korkmaz S, Zitron E, Bangert A, Seyler C, Li S, Hegedüs P, Scherer D, Li J, Fink T, Schweizer PA, Giannitsis E, Karck M, Szabó G, Katus HA, Kaya Z. Provocation of an autoimmune response to cardiac voltage-gated sodium channel NaV1.5 induces cardiac conduction defects in rats. J Am Coll Cardiol 62: 340 - 9 (2013)
Zitron E, Günth M, Scherer D, Kiesecker C, Kulzer M, Bloehs R, Scholz EP, Thomas D, WeidenhammerC, Kathöfer S, Bauer A, Katus HA, Karle CA: Kir2.x inward rectifier potassium channels are differentially regulated by adrenergic a1A receptors. J Mol Cell Cardiol 44: 84 - 94 (2008)
Zhang W, Zitron E, Hömme M, Kihm L, Morath C, Scherer D, Hegge S, Thomas D, Schmitt CP, Zeier M, Katus H, Karle C, Schwenger V: Aquaporin-1 channel function is positively regulated by protein kinase C. J Biol Chem 29: 20933 - 40 (2007)
Kiesecker C, Zitron E, Scherer D, Lueck S, Bloehs R, Scholz EP, Pirot M, Kathöfer S, Thomas D, Kreye VA, Kiehn J, Borst MM, Katus HA, Schoels W, Karle CA: Regulation of cardiac inwardly rectifying potassium current IK1 and Kir2.x channels by endothelin-1. J Mol Med 84(1): 46 - 56 (2006)
Zitron E, Scholz EP, Owen RW, Lück S, Kiesecker C, Thomas D, Kathöfer S, Niroomand F, Kiehn J, Kreye VA, Katus HA, Schoels W, Karle CA: QTc prolongation by grapefruit juice and its potiential pharmacological basis: HERG channel blockade by flavonoids. Circulation 111: 835-838 (2005)
In cardiomyocytes, ion channels are not separated proteins. In contrast, they form signalling complexes with specific molecules. In cardiomyopathies, structural and functional remodeling of these complexes leads to arrhythmias. The aim of our research is to identify new molecular targets within these signalling complexes and to validate them for antiarrhythmic therapies.
Our present projects focus on molecular signalling complexes of Kir2 channels, which underlie the inwardly rectifying IK1 current in cardiomyocytes, and on aquaporin-1 channels, which form a water channel in cardiomyocytes. In an innovative interdisciplinary cooperation with the Neurooncology Group at the DKFZ, we investigate Kir2 signalling complexes in the CNS (medulloblastoma) and heart muscle.