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Central neuregulin-1/ErbB signaling modulates cardiac function via sympathetic activity in pressure overload-induced heart failure

Matsukawa, Ryuichia; Hirooka, Yoshitakab; Ito, Kojia; Honda, Nobuhiroa; Sunagawa, Kenjia

doi: 10.1097/HJH.0000000000000072
ORIGINAL PAPERS: Neural mechanisms

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.

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aDepartment of Cardiovascular Medicine

bDepartment of Advanced Cardiovascular Regulation and Therapeutics, Kyushu University Graduate School of Medical Sciences, Maidashi, Higashi-ku, Fukuoka, Japan

Correspondence to Yoshitaka Hirooka, MD, PhD, Department of Advanced Cardiovascular Regulation and Therapeutics, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Tel: +81 92 6425356; fax: +81 92 6425374; e-mail:

Abbreviations: LVDd, left ventricle end-diastolic diameter; LVDs, left ventricle end-systolic diameter; LVEDP, left ventricle end-diastolic pressure; LVWT, left ventricle wall thickness; negative dP/dt max, maximum rate of pressure reduction; NRG-1, neuregulin-1; positive dP/dt max, maximum rate of pressure increase; rhNRG-1β, recombinant NRG-1β; RVLM, rostral ventrolateral medulla; SNS, sympathetic nervous system; uNE, urinary norepinephrine excretion; WKY rats, Wistar–Kyoto rats

Received 28 November, 2012

Accepted 8 November, 2013

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