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EMBO Mol Med. 2014 Sep 5;6(10):1231-45. doi: 10.15252/emmm.201403848.

CaM Kinase II mediates maladaptive post-infarct remodeling and pro-inflammatory chemoattractant signaling but not acute myocardial ischemia/reperfusion injury.

Author information

  • 1Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
  • 2DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
  • 3Department of Cardiology, Saarland University, Homburg, Germany.
  • 4Medical Research Center, University of Heidelberg Medical Faculty Mannheim, Mannheim, Germany.
  • 5British Heart Foundation Centre of Research Excellence, Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK.
  • 6Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
  • 7Research 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.

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.

KEYWORDS:

Ca2+/calmodulin‐dependent protein kinase II; apoptosis; cardiac remodeling; gene replacement; ischemia/reperfusion injury

PMID:
25193973
PMCID:
PMC4287929
DOI:
10.15252/emmm.201403848
[PubMed - indexed for MEDLINE]
Free PMC Article
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