title: CaM Kinase II mediates maladaptive post-infarct remodeling and pro-inflammatory chemoattractant signaling but not acute myocardial ischemia/reperfusion injury.
abstract: CaMKII was suggested to mediate ischemic myocardial injury and adverse cardiac remodeling. Here, we investigated the roles of different CaMKII isoforms and splice variants in ischemia/reperfusion (I/R) injury by the use of new genetic CaMKII mouse models. Although CaMKIIδC was upregulated 1 day after I/R injury, cardiac damage 1 day after I/R was neither affected in CaMKIIδ-deficient mice, CaMKIIδ-deficient mice in which the splice variants CaMKIIδB and C were re-expressed, nor in cardiomyocyte-specific CaMKIIδ/γ double knockout mice (DKO). In contrast, 5 weeks after I/R, DKO mice were protected against extensive scar formation and cardiac dysfunction, which was associated with reduced leukocyte infiltration and attenuated expression of members of the chemokine (C-C motif) ligand family, in particular CCL3 (macrophage inflammatory protein-1α, MIP-1α). Intriguingly, CaMKII was sufficient and required to induce CCL3 expression in isolated cardiomyocytes, indicating a cardiomyocyte autonomous effect. We propose that CaMKII-dependent chemoattractant signaling explains the effects on post-I/R remodeling. Taken together, we demonstrate that CaMKII is not critically involved in acute I/R-induced damage but in the process of post-infarct remodeling and inflammatory processes.
authors.affiliation: Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Weinreuter
authors.affiliation: Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Kreusser
authors.affiliation: Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Beckendorf
authors.affiliation: Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Friederike C
authors.initials: FC
authors.lastname: Schreiter
authors.affiliation: DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Leuschner
authors.affiliation: Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Lorenz H
authors.initials: LH
authors.lastname: Lehmann
authors.affiliation: Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Kai P
authors.initials: KP
authors.lastname: Hofmann
authors.affiliation: Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Julia S
authors.initials: JS
authors.lastname: Rostosky
authors.affiliation: Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Diemert
authors.affiliation: Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Chang
authors.initials: C
authors.lastname: Xu
authors.affiliation: DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Volz
authors.affiliation: DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Jungmann
authors.affiliation: Department of Cardiology, Saarland University, Homburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Nickel
authors.affiliation: Medical Research Center, University of Heidelberg Medical Faculty Mannheim, Mannheim, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Sticht
authors.affiliation: Medical Research Center, University of Heidelberg Medical Faculty Mannheim, Mannheim, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Gretz
authors.affiliation: Department of Cardiology, Saarland University, Homburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Maack
authors.affiliation: British Heart Foundation Centre of Research Excellence, Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schneider
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.affiliation: DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Müller
authors.affiliation: DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany johannes.backs@med.uni-heidelberg.de.
authors.forename: Johannes
authors.initials: J
authors.lastname: Backs
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D015153:Blotting, Western; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D054405:Chemokine CCL3 / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D002630:Chemotactic Factors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006321:Heart / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D054405:Chemokine CCL3; D018925:Chemokines; D002630:Chemotactic Factors; D018836:Inflammation Mediators; D007527:Isoenzymes; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: Ca2+/calmodulin‐dependent protein kinase II; apoptosis; cardiac remodeling; gene replacement; ischemia/reperfusion injury