Abstract 1272: Inhibition of Nuclear Factor-Kappa B Improves Endoplasmic Reticulum Stress-Induced Apoptosis and LV Remodeling in Heart Failure

Abstract

The endoplasmic reticulum (ER) normally participates in protein folding, calcium storage, and cell signaling. Cellular insult, however, induces the ER-stress response that can produce apoptosis and cell death with persistent activation. Nuclear factor (NF)-κB, a transcriptional regulator of cell survival responses is implicated in the maladaptive responses of ER-stress. However, its role in modulating ER stress-responses in the failing heart is unknown. Hypothesis: NF-κB activation in heart failure (HF) exacerbates LV remodeling in part by augmenting maladaptive ER-stress responses. Coronary ligation (or sham operation) was performed in male transgenic (TG) mice with cardiac-specific overexpression of a dominant-negative (DN) IκBα (n=16) and in non-transgenic (NTG) littermates (n=16). Compared to NTG sham, 4 weeks after surgery, NTG HF hearts exhibited significant (p < 0.05): LV dilatation and systolic dysfunction; myocyte hypertrophy and fibrosis; and NF-κB activation (~2-fold). Immunoblotting also revealed reduced expression (p < 0.05) of ER resident chaperones Grp78 and Grp94 and increased expression (p < 0.001) of CHOP, a pro-apoptotic transcription factor induced by ER stress, that correlated with increased (p < 0.05) apoptosis by TUNEL staining (1.1 ± 0.5 vs. 0.03 ± 0.03%, p < 0.05)). In contrast, compared to NTG HF, TG HF hearts had markedly reduced (p < 0.01) NF-κB activation, significantly less (p <0.05) LV dilatation, systolic dysfunction, and fibrosis but similar degrees of myocyte hypertrophy. Importantly, NF-κB abrogation also resulted in significantly increased expression of Grp78 and Grp94 and complete prevention of CHOP induction. Also, compared to TG sham, TG HF showed a mild but non-significant (p <0.45) increase in apoptotic rates (0.4 ± 0.3 %) by TUNEL. Parallel H9c2 cell studies indicated that induction of ER stress with tunicamycin activated NF-κB and increased apoptosis as measured by caspase-3, -12, and PARP cleavage. In contrast, DN IκBα adult cardiomyocytes maintained viability upon tunicamycin exposure suggesting a pro-apoptotic role for NF-κB activation during ER stress. Conclusion: Persistent NF-κB activation in post-infarction HF exacerbates cardiac ER stress and apoptosis and worsens LV remodeling.