title: Cardiomyocyte NF-κB p65 promotes adverse remodelling, apoptosis, and endoplasmic reticulum stress in heart failure.
abstract: OBJECTIVE
  the role of nuclear factor (NF)-κB in heart failure (HF) is not well defined. We sought to determine whether myocyte-localized NF-κB p65 activation in HF exacerbates post-infarction remodelling and promotes maladaptive endoplasmic reticulum (ER) stress.
  
  
  RESULTS
  non-transgenic (NTg) and transgenic (Tg) mice with myocyte-restricted overexpression of a phosphorylation-resistant inhibitor of κBα (IκBα(S32A,S36A)) underwent coronary ligation (to induce HF) or sham operation. Over 4 weeks, the remote myocardium of ligated hearts exhibited robust NF-κB activation that was almost exclusively p65 beyond 24 h. Compared with sham at 4 weeks, NTg HF hearts were dilated and dysfunctional, and exhibited hypertrophy, fibrosis, up-regulation of inflammatory cytokines, increased apoptosis, down-regulation of ER protein chaperones, and up-regulation of the ER stress-activated pro-apoptotic factor CHOP. Compared with NTg HF, Tg-IκBα(S32A,S36A) HF mice exhibited: (i) improved survival, chamber remodelling, systolic function, and pulmonary congestion, (ii) markedly diminished NF-κB p65 activation, cytokine expression, and fibrosis, and (iii) a three-fold reduction in apoptosis. Moreover, Tg-IκBα(S32A,S36A) HF hearts exhibited maintained expression of ER chaperones and CHOP when compared with sham. In cardiomyocytes, NF-κB activation was required for ER stress-mediated apoptosis, whereas abrogation of myocyte NF-κB shifted the ER stress response to one of adaptation and survival.
  
  
  CONCLUSIONS
  persistent myocyte NF-κB p65 activation in HF exacerbates cardiac remodelling by imparting pro-inflammatory, pro-fibrotic, and pro-apoptotic effects. p65 modulation of cell death in HF may occur in part from NF-κB-mediated transformation of the ER stress response from one of adaptation to one of apoptosis.
authors.affiliation: Department of Medicine, Louisville VAMC and Institute of Molecular Cardiology, University of Louisville, ACB, 3rd Floor, 550 South Jackson Street, Louisville, Louisville, KY 40202, USA.
authors.forename: Tariq
authors.initials: T
authors.lastname: Hamid
authors.forename: Shang Z
authors.initials: SZ
authors.lastname: Guo
authors.forename: Justin R
authors.initials: JR
authors.lastname: Kingery
authors.forename: Xilin
authors.initials: X
authors.lastname: Xiang
authors.forename: Buddhadeb
authors.initials: B
authors.lastname: Dawn
authors.forename: Sumanth D
authors.initials: SD
authors.lastname: Prabhu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D016207:Cytokines / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000502:physiology; D005355:Fibrosis; D006333:Heart Failure / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D013312:Stress, Physiological; D051996:Transcription Factor RelA / Q000502:physiology*; D020257:Ventricular Remodeling / Q000235:genetics / Q000502:physiology
chemical_list: D016207:Cytokines; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D050505:Mutant Proteins; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha
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