Abstract 790: Inhibition of Nuclear Factor-kB Exacerbates Beta-Adrenergic Receptor Mediated Cardiac Remodeling In Vivo
We have previously shown that sustained β-adrenergic receptor (β-AR) stimulation induces both inflammatory activation and pathological remodeling in the heart. Nuclear factor (NF)-κB, a central transcriptional mediator of inflammation, is activated by β-AR stimulation; however, the role of NF-κB in β-AR-induced remodeling is unknown. We tested the hypothesis that NF-κB activation in the heart modulates the remodeling response to β-AR stimulation. Osmotic minipumps with either isoproterenol (ISO, 625 μg/kg/h) or saline (SAL) were placed in adult male transgenic mice with NF-κB inhibition due to cardiac-specific overexpression of a phosphorylation-resistant IκBα (IκBα DN TG, n = 15) or in non-transgenic (NTG) littermates (n = 15) for 3 days. Echocardiography showed no baseline cardiac phenotype in the TG mice. NTG ISO hearts exhibited (vs. NTG SAL):
significantly (p < 0.05) increased heart rate (HR), fractional shortening (FS), and relative wall thickness (RWT) by echocardiography, indicating augmented systolic function and concentric remodeling,
hypertrophy (LV/body weight [BW] ratio (3.9 ± 0.2 vs. 3.2 ± 0.1 mg/g; myocyte cross-sectional area [CSA] 331 ± 87 vs. 225 ± 63 μm2, p < 0.001),
increased fibrosis (collagen density 2.8 ± 1.8 vs. 1.9 ± 1.4 %, p < 0.001), and
inflammatory activation (~3-fold higher interleukin [IL]-6 mRNA, p < 0.001).
IκBα DN TG ISO hearts also had significant increases in HR, FS, and RWT comparable to NTG ISO. However, as compared to NTG ISO, TG ISO hearts had substantially increased (p < 0.001) hypertrophy (myocyte CSA 389 ± 87 μm2, p < 0.001) and fibrosis (collagen 5.5 ± 3.6 %). Moreover, unlike NTG ISO, TG ISO mice exhibited increased lung weight/BW ratio (5.8 ± 0.6 vs. TG SAL 4.8 ± 0.4 mg/g, p < 0.01) suggesting diastolic heart failure and lung edema. Surprisingly, despite NF-κB suppression, mRNA levels of tumor necrosis factor, IL-1β, and IL-6 were markedly increased in TG ISO hearts (p < 0.001), to a greater magnitude than NTG ISO hearts.
Conclusion: NF-κB abrogation in the heart exacerbates the hypertrophic and fibrotic response to sustained in vivo β-AR stimulation and may worsen diastolic function. Furthermore, β-AR-induced pro-inflammatory cytokine expression in the heart can occur in an NF-κB-independent manner.