title: Cardiomyocyte-specific p65 NF-κB deletion protects the injured heart by preservation of calcium handling.
abstract: NF-κB is a well-known transcription factor that is intimately involved with inflammation and immunity. We have previously shown that NF-κB promotes inflammatory events and mediates adverse cardiac remodeling following ischemia reperfusion (I/R). Conversely, others have pointed to the beneficial influence of NF-κB in I/R injury related to its anti-apoptotic effects. Understanding the seemingly disparate influence of manipulating NF-κB is hindered, in part, by current approaches that only indirectly interfere with the function of its most transcriptionally active unit, p65 NF-κB. Mice were generated with cardiomyocyte-specific deletion of p65 NF-κB. Phenotypically, these mice and their hearts appeared normal. Basal and stimulated p65 expression were significantly reduced in whole hearts and completely ablated in isolated cardiomyocytes. When compared with wild-type mice, transgenic animals were protected from both global I/R by Langendorff as well as regional I/R by coronary ligation and release. The protected, transgenic hearts had less cytokine activity and decreased apoptosis. Furthermore, p65 ablation was associated with enhanced calcium reuptake by the sarcoplasmic reticulum. This influence on calcium handling was related to increased expression of phosphorylated phospholamban in conditional p65 null mice. In conclusion, cardiomyocyte-specific deletion of the most active, canonical NF-κB subunit affords cardioprotection to both global and regional I/R injury. The beneficial effects of NF-κB inhibition are related, in part, to modulation of intracellular calcium homeostasis.
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, University of Utah, Salt Lake City, Utah;
authors.forename: Xiu Q
authors.initials: XQ
authors.lastname: Zhang
authors.forename: Ruhang
authors.initials: R
authors.lastname: Tang
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Amanda
authors.initials: A
authors.lastname: Szucsik
authors.forename: Hadi
authors.initials: H
authors.lastname: Javan
authors.forename: Noriko
authors.initials: N
authors.lastname: Saegusa
authors.forename: Ken W
authors.initials: KW
authors.lastname: Spitzer
authors.forename: Craig H
authors.initials: CH
authors.lastname: Selzman
mesh_terms: D000818:Animals; D017209:Apoptosis; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005838:Genotype; D006706:Homeostasis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D051996:Transcription Factor RelA / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D016207:Cytokines; D051996:Transcription Factor RelA; D000099211:Phospholamban; C498144:Rela protein, mouse
keywords: calcium; ischemia-reperfusion; nuclear factor-κB; phospholamban
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