| First Author | Gray CB | Year | 2017 |
| Journal | J Mol Cell Cardiol | Volume | 103 |
| Pages | 48-55 | PubMed ID | 28077321 |
| Mgi Jnum | J:250773 | Mgi Id | MGI:6101775 |
| Doi | 10.1016/j.yjmcc.2017.01.002 | Citation | Gray CB, et al. (2017) CaMKIIdelta subtypes differentially regulate infarct formation following ex vivo myocardial ischemia/reperfusion through NF-kappaB and TNF-alpha. J Mol Cell Cardiol 103:48-55 |
| abstractText | Deletion of Ca(2+)/calmodulin-dependent protein kinase II delta (CaMKIIdelta) has been shown to protect against in vivo ischemia/reperfusion (I/R) injury. It remains unclear which CaMKIIdelta isoforms and downstream mechanisms are responsible for the salutary effects of CaMKIIdelta gene deletion. In this study we sought to compare the roles of the CaMKIIdeltaB and CaMKIIdeltaC subtypes and the mechanisms by which they contribute to ex vivo I/R damage. WT, CaMKIIdeltaKO, and mice expressing only CaMKIIdeltaB or deltaC 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 CaMKIIdelta conferred significant protection from ex vivo I/R. Re-expression of CaMKIIdeltaC in the CaMKIIdeltaKO background reversed this effect and exacerbated myocardial damage and dysfunction following I/R, while re-expression of CaMKIIdeltaB was protective. Selective activation of CaMKIIdeltaC 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-kappaB) signaling and tumor necrosis factor alpha (TNF-alpha) expression by CaMKIIdeltaB and CaMKIIdeltaC. Selective activation of CaMKIIdeltaC was also observed and associated with NF-kappaB activation in neonatal rat ventricular myocytes (NRVMs) subjected to oxidative stress. Pharmacological inhibition of NF-kappaB or TNF-alpha significantly ameliorated infarct formation in WT mice and those that re-express CaMKIIdeltaC, demonstrating distinct roles for CaMKIIdelta subtypes in I/R and implicating acute activation of CaMKIIdeltaC and NF-kappaB in the pathogenesis of reperfusion injury. |
