Abstract 14481: Inhibition of the Toll-Like Receptor 4 in the Brainstem Causes the Sympathoinhibition and Improves the Left Ventricular Systolic Dysfunction in Heart Failure
Background: Heart failure (HF) is associated with sympathoexcitation due to AT1 receptor-induced oxidative stress in the brainstem. Oxidative stress in the brain is known to activate inflammatory cascade mediated by toll-like receptor 4 (TLR4). Previously, we suggested that AT1 receptor in the brainstem enhanced the central sympathetic outflow through at least in part the inflammation mediated by TLR4 in HF model.
Hypothesis: The aim of this study was to examine whether the inhbition of the TLR4 in the brainstem decreases sympathetic activity and improves the left ventricular (LV) systolic dysfunction in rats with HF or not.
Methods and Results: We created, as a model of HF, myocardial infarction (MI) by ligating the left coronary artery. We designed 3 different small interference RNA (siRNA) against the rat TLR4 and selected the siRNA determined by Western blot analysis with the highest efficacy in vitro. On day 21 after ligation, the expression level of TLR4 in the brainstem and urinary norepinephrine excretion (UNE), a parameter of sympathetic activity, were significantly higher in HF than in sham (TLR4 expression: 1.00±0.02 vs. 0.65±0.06, n=4 for each, p<0.05, and UNE: 1078±134 vs. 615±38 pg/day, n=5 for each, p<0.05). TLR4 in the brainstem was inhibited by intracerebroventricular (ICV) injection of the siRNA-TLR4 at day 7 and 14 after ligation. The lung weight relative to body weight and UNE were significantly lower (lung weight; 5.1±0.3 mg/g vs. 8.4±0.3 mg/g, n=4, for each, p<0.05), and the echocardiographic LV fractional shortening was significantly higher (17.1±1.0 vs. 23.2±0.4%, n=4 for each, p<0.05) in siRNA-TLR4-treated HF than in vehicle-treated HF.
Conclusion: The inhibition of TLR4 in the brainstem due to the ICV infusion of siRNA-TLR4 might in part cause the sympathoinhibition and improve the LV systolic dysfunction in rats with HF.
- © 2011 by American Heart Association, Inc.