Abstract 14560: Central NRG-1/ErbB Signaling Has a Pivotal Role in Sympathoexcitation in Heart Failure
Background: It has been reported that NRG-1/ErbB signaling in cardiomyocytes is impaired in pressure overload induced heart failure (HF). We previously reported that activation of NRG-1/ErbB signaling in the rostral ventrolateral medulla (RVLM) of brainstem elicited a depressor effect via sympathoinhibition. Furthermore, we found that dysfunction of this signaling due to reduced ErbB2 expression in the brainstem of hypertensive rats may contribute to the hypertensive mechanisms by sympathoexcitation. However, how central NRG-1/ErbB signaling impacts sympathoexcitation in HF remains unknown. Therefore, we examined the role of central NRG-1/ErbB signaling in modulating sympathetic nerve activity in pressure overload induced HF.
Methods and Results: We created, in Wistar-Kyoto rats, pressure overload induced HF by banding the abdominal aorta and followed up the animals for 15 weeks (W). Aortic banding exacerbated left ventricle (LV) hypertrophy, LV dilation and impairment of LV function (reducing fractional shortening (%FS), increasing LV end diastolic pressure (LVEDP) and decreasing dp/dtmax) and increased urinary norepinephrine excretion (uNE) compared to sham operated rats. Aortic banding reduced the expression level of NRG-1 in the brainstem at 10W and that of ErbB2 at 5W, whereas did not affect ErbB4 during observation. Supplemental infusions of NRG-1 (0.5 μ g/kg/day, continuous intracisternal infusion) at 5W (when reduction of ErbB2 expression was started ) for 2 weeks attenuated LV hypertrophy (4.8±0.2 vs. 4.4±0.1 mm, p<0.05), improved LV dilatation (LVDs: 4.4±0.2 vs. 3.4±0.2 mm, p<0.01), prevented LV dysfunction (%FS: 36.9±2.2 vs. 48.6±2.4 %; p<0.01, LVEDP: 20.0±3.4 vs. 5.5±0.6 mmHg; p<0.05, dp/dtmax: 5847±556 vs. 9592±330 mmHg/s; p<0.01) and lowered uNE (1.61±0.19 vs. 0.83±0.08 μ g /day, p<0.01) at 15W after banding.
Conclusion: NRG-1/ErbB signaling in the brainstem is impaired during progression of pressure overload induced HF. Activation of central NRG-1/ErbB signaling may improve cardiac function through sympathoinhibition.
- © 2011 by American Heart Association, Inc.