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

Aims The role of nuclear factor (NF)-kappa B in heart failure (HF) is not well defined. We sought to determine whether myocyte-localized NF-kappa B 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 kappa B alpha (I kappa B alpha(S32A, S36A)) underwent coronary ligation (to induce HF) or sham operation. Over 4 weeks, the remote myocardium of ligated hearts exhibited robust NF-kappa B 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-I kappa B alpha(S32A, S36A) HF mice exhibited: (i) improved survival, chamber remodelling, systolic function, and pulmonary congestion, (ii) markedly diminished NF-kappa B p65 activation, cytokine expression, and fibrosis, and (iii) a three-fold reduction in apoptosis. Moreover, Tg-I kappa B alpha(S32A, S36A) HF hearts exhibited maintained expression of ER chaperones and CHOP when compared with sham. In cardiomyocytes, NF-kappa B activation was required for ER stress-mediated apoptosis, whereas abrogation of myocyte NF-kappa B shifted the ER stress response to one of adaptation and survival. Conclusion Persistent myocyte NF-kappa B p65 activation in HF exacerbates cardiac remodelling by imparting pro-inflammatory, profibrotic, and pro-apoptotic effects. p65 modulation of cell death in HF may occur in part from NF-kappa B-mediated transformation of the ER stress response from one of adaptation to one of apoptosis.