Cardiomyocyte NF-κB p65 promotes adverse remodelling, apoptosis, and endoplasmic reticulum stress in heart failure.

Academic Article


  • AIMS: 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. METHODS AND 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. CONCLUSION: 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.
  • Published In


  • Animals, Apoptosis, Cell Line, Cytokines, Endoplasmic Reticulum, Fibrosis, Heart Failure, Humans, I-kappa B Proteins, In Vitro Techniques, Inflammation Mediators, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutant Proteins, Myocardial Infarction, Myocytes, Cardiac, NF-KappaB Inhibitor alpha, Stress, Physiological, Transcription Factor RelA, Ventricular Remodeling
  • Digital Object Identifier (doi)

    Author List

  • Hamid T; Guo SZ; Kingery JR; Xiang X; Dawn B; Prabhu SD
  • Start Page

  • 129
  • End Page

  • 138
  • Volume

  • 89
  • Issue

  • 1