title: Ca2+/Calmodulin-dependent protein kinase II δ mediates myocardial ischemia/reperfusion injury through nuclear factor-κB.
abstract: BACKGROUND
  Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) has been implicated as a maladaptive mediator of cardiac ischemic injury. We hypothesized that the inflammatory response associated with in vivo ischemia/reperfusion (I/R) is initiated through CaMKII signaling.
  
  
  OBJECTIVE
  To assess the contribution of CaMKIIδ to the development of inflammation, infarct, and ventricular dysfunction after in vivo I/R and define early cardiomyocyte-autonomous events regulated by CaMKIIδ using cardiac-specific knockout mice.
  
  
  RESULTS
  Wild-type and CaMKIIδ knockout mice were subjected to in vivo I/R by occlusion of the left anterior descending artery for 1 hour followed by reperfusion for various times. CaMKIIδ deletion protected the heart against I/R damage as evidenced by decreased infarct size, attenuated apoptosis, and improved functional recovery. CaMKIIδ deletion also attenuated I/R-induced inflammation and upregulation of nuclear factor-κB (NF-κB) target genes. Further studies demonstrated that I/R rapidly increases CaMKII activity, leading to NF-κB activation within minutes of reperfusion. Experiments using cyclosporine A and cardiac-specific CaMKIIδ knockout mice indicate that NF-κB activation is initiated independent of necrosis and within cardiomyocytes. Expression of activated CaMKII in cardiomyocytes leads to IκB kinase phosphorylation and concomitant increases in nuclear p65. Experiments using an IκB kinase inhibitor support the conclusion that this is a proximal site of CaMKII-mediated NF-κB activation.
  
  
  CONCLUSIONS
  This is the first study demonstrating that CaMKIIδ mediates NF-κB activation in cardiomyocytes after in vivo I/R and suggests that CaMKIIδ serves to trigger, as well as to sustain subsequent changes in inflammatory gene expression that contribute to myocardial I/R damage.
authors: Department of Pharmacology, University of California-San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0636, USA.
authors: Haiyun
authors: H
authors: Ling
authors: Charles B B
authors: CB
authors: Gray
authors: Alexander C
authors: AC
authors: Zambon
authors: Michael
authors: M
authors: Grimm
authors: Yusu
authors: Y
authors: Gu
authors: Nancy
authors: N
authors: Dalton
authors: Nicole H
authors: NH
authors: Purcell
authors: Kirk
authors: K
authors: Peterson
authors: Joan Heller
authors: JH
authors: Brown
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology*; D016572:Cyclosporine / Q000494:pharmacology; D020869:Gene Expression Profiling; D006321:Heart; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000209:etiology* / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D020127:Recovery of Function / Q000502:physiology; D051996:Transcription Factor RelA / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; D051996:Transcription Factor RelA; D016572:Cyclosporine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
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