Abstract 15157: AT1 Receptor-Activated Toll-Like Receptor 4 in the Brainstem Causes Sympathoexcitation in Mice With Heart Failure
Background: Previous studies suggest that heart failure (HF) is associated with sympathoexcitation due to oxidative stress in the brain induced by AT1 receptors (AT1R). In the brain, oxidative stress occurs upstream of inflammatory signaling pathways mediated by toll-like receptor 4 (TLR4).
Hypothesis: AT1R-induced sympathoexcitation is mediated by TLR4 in the brainstem of HF model , and if so, the inflammation in the brain is associated with sympathoexcitation.
Method and Results: As a model of HF, the left coronary artery was ligated to induce a large myocardial infarction and subsequent HF in ICR mice. On day 10 after the left coronary artery ligation, we initiated 14-day chronic intracerebroventricular (ICV) infusion of losartan (CHF-Los) or vehicle (CHF-Veh) via osmotic minipumps. Expression of TLR4 in the brainstem determined by Western blot analysis was significantly higher in HF mice than in sham mice (1.06±0.04 vs 0.56±0.11, n=5 for each, P<0.05) and significantly lower in CHF-Los than in CHF-Veh (0.29±0.04 vs 0.65±0.05, n=7 for each, P<0.05). Expression of NF-κB in the brainstem determined by an electrophoretic mobility shift assay was significantly higher in HF mice than in sham mice, and was significantly inhibited in CHF-Los compared to CHF-Veh. Urinary norepinephrine excretion, a measure of sympathetic nervous system activity, was significantly higher in HF mice than in sham mice (802±143 pg/day vs 413±29 pg/day, n=4 for each, P<0.05) and was significantly lower in CHF-Los than in CHF-Veh (425±39 pg/day vs 786±131 pg/day, n=4 for each, P<0.05). Left ventricular (LV) dimensions were smaller (diastole 5.4±0.1 mm vs 5.8±0.1 mm, systole; 4.0±0.2 mm vs 4.8±0.1 mm, n=5, p<0.05 for each) and % fractional shortening was greater (28.5±2.1 % vs 16.7±0.9 %, n=5, P<0.05 for each) in CHF-Los than in CHF-Veh.
Conclusion: Sympathoexcitation and LV dysfunction in HF induced by AT1 receptors in the brainstem is mediated, at least in part, by TLR4.
- © 2010 by American Heart Association, Inc.