CaMKII delta subtypes differentially regulate infarct formation following ex vivo myocardial ischemia/reperfusion through NF-kappa B and TNF-alpha

Charles B. B. Gray, Takeshi Suetomi, Sunny Xiang, Shikha Mishra, Erik A. Blackwood, Christopher C. Glembotski, Shigeki Miyamoto, B. Daan Westenbrink, Joan Heller Brown

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Deletion of Ca2+/calmodulin-dependent protein kinase II delta (CaMKII delta) has been shown to protect against in vivo ischemia/reperfusion (I/R) injury. It remains unclear which CaMKII delta isoforms and downstream mechanisms are responsible for the salutary effects of CaMKII delta gene deletion. In this study we sought to compare the roles of the CaMKII delta(B) and CaMKII delta(C) subtypes and the mechanisms by which they contribute to ex vivo I/R damage. WT, CaMKII delta KO, and mice expressing only CaMKII delta(B) or delta(C) were subjected to ex vivo global ischemia for 25 min followed by reperfusion. Infarct formation was assessed at 60 min reperfusion by triphenyl tetrazolium chloride (TTC) staining. Deletion of CaMKII delta conferred significant protection from ex vivo I/R. Re-expression of CaMKII delta(C) in the CaMKII delta KO background reversed this effect and exacerbated myocardial damage and dysfunction following I/R, while re-expression of CaMKII delta(B) was protective. Selective activation of CaMKII delta(C) in response to I/R was evident in a subcellular fraction enriched for cytosolic/membrane proteins. Further studies demonstrated differential regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) signaling and tumor necrosis factor alpha (TNF-alpha) expression by CaMKII delta(B) and CaMKII8c. Selective activation of CaMKII delta(C) was also observed and associated with NF-kappa B activation in neonatal rat ventricular myocytes (NRVMs) subjected to oxidative stress. Pharmacological inhibition of NF-kappa B or TNF-alpha significantly ameliorated infarct formation in WT mice and those that re-express CaMKII8c, demonstrating distinct roles for CaMKII delta subtypes in I/R and implicating acute activation of CaMKII delta(C) and NF-kappa B in the pathogenesis of reperfusion injury. (C) 2017 Published by Elsevier Ltd.

Original languageEnglish
Pages (from-to)48-55
Number of pages8
JournalJournal of molecular and cellular cardiology
Publication statusPublished - Feb-2017


  • CaMKII
  • NF-kappa B
  • TNF-alpha
  • Ischemia/reperfusion
  • Heart

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