Abstract 9762: Brain Tumor Necrosis Factor-α Augments Sympathoexcitation and Left Ventricular Remodeling of Ischemia-induced Heart Failure via Dysfunction of Keap1/Nrf2-mediated Antioxidant in Brain Astrocyte
[Backgrounds] We have demonstrated, in ischemic heart failure (HF), angiotensin II increases oxidative stress and induces apoptosis of brain astrocyte, sympathoexcitation and left ventricular (LV) remodeling. In astrocyte, the oxidant-sensing Keap1/NF-E2-related factor 2 (Nrf2) pathway mediates antioxidant function. Recent studies have indicated that brain proinflammatory cytokines also contribute to sympathoexcitation. The aim of the present study was to determine whether brain tumor necrosis factor (TNF)-α augments sympathoexcitation and LV remodeling caused by apoptosis of brain astrocyte in ischemia-induced HF, and if so, whether TNF-α impairs Keap1/Nrf2-mediated antioxidant function of brain astrocyte. [Methods and Results] We treated, for 4 weeks, Sprague-Dawley rats with HF (by coronary ligation) with a continuous intracerebroventricular infusion of angiotensin II type 1 receptor blocker (ARB), ARB+etanercept (ETN; TNF-a receptor blocker), vehicle (Veh) or sham. Urinary norepinephrine excretion (UNE; an index of sympathoexcitation), brain oxidative stress, and glial fibrillary acidic protein expression (GFAP; marker of astrocyte apoptosis) in the brain were significantly higher and LV end-systolic dimension (LVESD) were significantly larger in Veh than in sham (UNE; 2.3±0.3 μg/day vs. 1.1±0.2 μg/day, n=5 for each, p<0.05). Brain Nrf2 expression was significantly lower in Veh than in Sham (0.3±0.1 U vs. 1.0 U, value is expressed relative to that in sham, n=5 for each, p<0.05). In comparison to Veh, ARB lowered UNE (1.8±0.1 μg/day vs. 2.3±0.3 μg/day, n=5 for each, p<0.05), brain oxidative stress, GFAP expression, and LVESD. Furthermore, all of these beneficial effects were augmented in ARB+ETN to the similar levels in sham (UNE; 1.4±0.2 μg/day, n=5). Brain Nrf2 expression was significantly higher in ARB+ETN than in Veh (0.7±0.1 U vs. 0.3±0.1 U, value is expressed relative to that in sham, n=5 for each, p<0.05), although it was not different between in ARB and Veh. [Conclusion] Brain TNF-α augments angiotensin II-induced sympathoexcitation and LV remodeling of ischemia-induced HF via dysfunction of Keap1/Nrf2-mediated antioxidant in brain astrocyte.
- © 2012 by American Heart Association, Inc.