Abstract 590: Abrogation of Nuclear Factor-Kappa B Activation in the Heart Alleviates Post-Infarction LV Remodeling
The failing heart is characterized by chronic activation of nuclear factor (NF)-κB, a central transcriptional mediator of inflammatory and stress responses. As NF-κB can signal to either survival or apoptotic pathways, however, whether such activation confers cardioprotective or detrimental effects is unknown. We tested the hypothesis that sustained activation of NF-κB exacerbates LV remodeling in heart failure (HF). We examined LV remodeling following permanent coronary ligation (or sham-operation) in adult male transgenic (TG) mice with NF-κB abrogation in the heart via the cardiac-specific overexpression of a phosphorylation-resistant IκBα (n=16), or in non-transgenic (NTG) littermates (n=16). Baseline echocardiography showed no inherent cardiac phenotype in the TG mice. Compared to NTG sham, 4 weeks after surgery, NTG HF hearts showed:
increased (p < 0.01) LV size (EDV 94 ± 35 vs. 35 ± 5 μL) and systolic dysfunction (LVEF 50 ± 9 vs. 75 ± 7 %) by echocardiography;
hypertrophy (LV/tibia length [TL] 5.3 ± 0.7 vs. 3.7 ± 0.3, p < 0.001; ~2-fold greater atrial natriuretic factor [ANF] mRNA, p < 0.05);
significantly (p < 0.05) increased (~2-fold) NF-κB DNA binding activity and mRNA levels of the NF-κB-responsive cytokines tumor necrosis factor (TNF), interleukin (IL)-1β, and IL-6; and
increased apoptotic rates 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 DNA activation, and significantly less (p < 0.05) LV dilatation (LVEDV 52 ± 20 μL) and systolic dysfunction (LVEF 61 ± 8 %), but a similar degree of hypertrophy as assessed by LV/TL and ANF expression. Moreover, as compared to TG sham, TG HF hearts exhibited no TNF, IL-1β, or IL-6 upregulation. Importantly, as compared to TG sham, TG HF showed only a mild increase in apoptotic rate (0.4 ± 0.3 %) that was not statistically significant (p = 0.45), suggesting that differences in the rate of cell loss between NTG and TG HF may account for comparable degrees of chamber hypertrophy despite differences in LV dilatation.
Conclusion: Persistent NF-κB activation imparts detrimental effects in post-infarction HF and worsens LV remodeling, related, at least in part, to augmentation of inflammatory cytokine expression and apoptosis.