Ryuichi Matsukawa1, Yoshitaka Hirooka, Koji Ito, Nobuhiro Honda, Kenji Sunagawa. 1. aDepartment of Cardiovascular Medicine bDepartment of Advanced Cardiovascular Regulation and Therapeutics, Kyushu University Graduate School of Medical Sciences, Maidashi, Higashi-ku, Fukuoka, Japan.
Abstract
OBJECTIVES: Neuregulin-1 (NRG-1)/ErbB signaling in the heart is reported to have a crucial role in heart failure. We recently demonstrated that NRG-1 signaling has sympathoinhibitory effects in the brain cardiovascular control center. How this central signaling impacts sympathoexcitation in heart failure, however, is unknown. Here we examined the role of central NRG-1/ErbB signaling in modulating the sympathetic nervous system in pressure overload-induced heart failure. METHODS AND RESULTS: Pressure overload-induced heart failure was induced in Wistar-Kyoto rats by banding the abdominal aorta. Rats were followed up for 15 weeks. Compared to sham-operated rats, aortic-banded rats showed left ventricle (LV) hypertrophy, LV dilation, and LV dysfunction [reducing fractional shortening (%fractional shortening), increased LV end-diastolic pressure, decreased positive and negative pressure differential (±dp/dt(max))], and increased urinary norepinephrine excretion. Aortic banding led to reduced expression of NRG-1 in the brainstem at 10 weeks after banding and reduced expression of ErbB2 at 5 weeks, but did not affect ErbB4. Central administration of recombinant NRG-1β at 5 weeks for 2 weeks attenuated LV hypertrophy, improved LV dilatation, prevented LV dysfunction (improvement of %fractional shortening and ±dp/dt(max), and reduction of LV end-diastolic pressure), and lowered urinary norepinephrine excretion at 10 weeks, and these effects were still observed at 15 weeks. CONCLUSION: NRG-1/ErbB signaling in the brainstem is impaired during the progression of pressure overload-induced heart failure. Activation of central NRG-1 signaling improves cardiac function through sympathoinhibition. These findings provide a new treatment concept and support the benefit of NRG-1 treatment in heart failure.
OBJECTIVES:Neuregulin-1 (NRG-1)/ErbB signaling in the heart is reported to have a crucial role in heart failure. We recently demonstrated that NRG-1 signaling has sympathoinhibitory effects in the brain cardiovascular control center. How this central signaling impacts sympathoexcitation in heart failure, however, is unknown. Here we examined the role of central NRG-1/ErbB signaling in modulating the sympathetic nervous system in pressure overload-induced heart failure. METHODS AND RESULTS: Pressure overload-induced heart failure was induced in Wistar-Kyoto rats by banding the abdominal aorta. Rats were followed up for 15 weeks. Compared to sham-operated rats, aortic-banded rats showed left ventricle (LV) hypertrophy, LV dilation, and LV dysfunction [reducing fractional shortening (%fractional shortening), increased LV end-diastolic pressure, decreased positive and negative pressure differential (±dp/dt(max))], and increased urinary norepinephrine excretion. Aortic banding led to reduced expression of NRG-1 in the brainstem at 10 weeks after banding and reduced expression of ErbB2 at 5 weeks, but did not affect ErbB4. Central administration of recombinant NRG-1β at 5 weeks for 2 weeks attenuated LV hypertrophy, improved LV dilatation, prevented LV dysfunction (improvement of %fractional shortening and ±dp/dt(max), and reduction of LV end-diastolic pressure), and lowered urinary norepinephrine excretion at 10 weeks, and these effects were still observed at 15 weeks. CONCLUSION:NRG-1/ErbB signaling in the brainstem is impaired during the progression of pressure overload-induced heart failure. Activation of central NRG-1 signaling improves cardiac function through sympathoinhibition. These findings provide a new treatment concept and support the benefit of NRG-1 treatment in heart failure.