CaMKII? subtypes differentially regulate infarct formation following ex vivo myocardial ischemia/reperfusion through NF-?B and TNF-?.

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

SUBMITTER: Gray CB 

PROVIDER: S-EPMC5564300 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature