Abstract 9763: Brain-targeted Intranasal Administration of Viral Inhibition Peptide of Toll-like Receptor 4 Improves Survival and Prevents Left Ventricular Remodeling Via Sympathoinhibition in Ischemia-induced Heart Failure
[Backgrounds] Abnormal sympathoexcitation causes left ventricular (LV) remodeling and worsen the prognosis of ischemia-induced heart failure (HF). Recent studies have suggested that inflammation in the brain induces sympathoexcitation in HF. We previously demonstrated that brain inflammatory cascade mediated by Toll-like receptor 4 (TLR4) is activated in HF associated with sympathoexcitation. However, brain-specific inhibitory agent of TLR4 has not been available. The aim of the present study was to investigate whether intranasal administration of viral inhibition peptide of TLR4 (VIPER) could inhibit brain-specific TLR4 or not, and whether the brain-targeted inhibition of TLR4 could improve survival rate and prevent LV remodeling via sympathoinhibition in ischemia-induced HF or not. [Methods and Results] Sprague-Dawley rats with HF by coronary artery ligation were initiated the treatment with a dairy intranasal administration of VIPER (VIP), dairy intraperitoneal administration of VIPER (IP) or vehicle (Veh) just after the operation. At day 1, the expressions of TLR4, MyD88 (second messenger of TLR4), and nuclear factor κB (NFκB) in the brain were already significantly lower in VIP than in IP and Veh. These effects in VIP group were confirmed continuously in terms of the treatments. At day 7, urinary norepinephrine excretion (UNE; parameter of sympathoexcitation) was significantly lower and LV end-systolic dimension (LVESD) were significantly smaller in VIP than in Veh (uNE; 1.6±0.2 μg/day vs. 2.5±0.2 μg/day, LVESD; 2.9±0.3 mm vs. 4.8±0.2 mm, n=15 for each, p<0.05 for each). At day 30, the survival rate was significantly higher in VIP than in Veh (84 % vs 61 %, P<0.05). All of these beneficial results in VIP group were not obtained in IP group. [Conclusion] Intranasal administration of viral inhibition peptide of TLR4 is able to inhibit brain-specific TLR4, and improves survival rate and prevents LV remodeling via sympathoinhibition in ischemia-induced HF. This method has a potential to be a novel treatment for ischemia-induced HF with sympathoinhibition.
- © 2012 by American Heart Association, Inc.