title: CaMKIIδ subtypes differentially regulate infarct formation following ex vivo myocardial ischemia/reperfusion through NF-κB and TNF-α.
abstract: Deletion of Ca2+/calmodulin-dependent protein kinase II delta (CaMKIIδ) has been shown to protect against in vivo ischemia/reperfusion (I/R) injury. It remains unclear which CaMKIIδ isoforms and downstream mechanisms are responsible for the salutary effects of CaMKIIδ gene deletion. In this study we sought to compare the roles of the CaMKIIδBand CaMKIIδCsubtypes and the mechanisms by which they contribute to ex vivo I/R damage. WT, CaMKIIδKO, and mice expressing only CaMKIIδBor δCwere 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 CaMKIIδ conferred significant protection from ex vivo I/R. Re-expression of CaMKIIδCin the CaMKIIδKO background reversed this effect and exacerbated myocardial damage and dysfunction following I/R, while re-expression of CaMKIIδBwas protective. Selective activation of CaMKIIδCin 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-κB) signaling and tumor necrosis factor alpha (TNF-α) expression by CaMKIIδBand CaMKIIδC. Selective activation of CaMKIIδCwas also observed and associated with NF-κB activation in neonatal rat ventricular myocytes (NRVMs) subjected to oxidative stress. Pharmacological inhibition of NF-κB or TNF-α significantly ameliorated infarct formation in WT mice and those that re-express CaMKIIδC, demonstrating distinct roles for CaMKIIδ subtypes in I/R and implicating acute activation of CaMKIIδCand NF-κB in the pathogenesis of reperfusion injury.
authors.affiliation: Department of Pharmacology, University of California San Diego, San Diego, CA, USA.
authors.forename: Charles B B
authors.initials: CB
authors.lastname: Gray
authors.affiliation: Department of Pharmacology, University of California San Diego, San Diego, CA, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Suetomi
authors.affiliation: Department of Pharmacology, University of California San Diego, San Diego, CA, USA; In Vivo Pharmacological & Clinical Laboratory Services, The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Sunny
authors.initials: S
authors.lastname: Xiang
authors.affiliation: ThermoFisher Scientific, Carlsbad, CA, USA.
authors.forename: Shikha
authors.initials: S
authors.lastname: Mishra
authors.affiliation: San Diego State University Heart Institute, Department of Biology, San Diego, CA, USA.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Blackwood
authors.affiliation: San Diego State University Heart Institute, Department of Biology, San Diego, CA, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Glembotski
authors.affiliation: Department of Pharmacology, University of California San Diego, San Diego, CA, USA.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Miyamoto
authors.affiliation: Department of Pharmacology, University of California San Diego, San Diego, CA, USA; Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: B Daan
authors.initials: BD
authors.lastname: Westenbrink
authors.affiliation: Department of Pharmacology, University of California San Diego, San Diego, CA, USA. Electronic address: jhbrown@ucsd.edu.
authors.forename: Joan Heller
authors.initials: JH
authors.lastname: Brown
mesh_terms: D000818:Animals; D001706:Biopsy; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004452:Echocardiography; D055786:Gene Knockout Techniques; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism* / Q000401:mortality; D015428:Myocardial Reperfusion Injury / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D018754:Ventricular Dysfunction
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: CaMKII; Heart; Inflammation; Ischemia/reperfusion; Myocardial Infarction; NF-κB; Signal transduction; TNF-α