title: Central neuregulin-1/ErbB signaling modulates cardiac function via sympathetic activity in pressure overload-induced heart failure.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: aDepartment of Cardiovascular Medicine bDepartment of Advanced Cardiovascular Regulation and Therapeutics, Kyushu University Graduate School of Medical Sciences, Maidashi, Higashi-ku, Fukuoka, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Matsukawa
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hirooka
authors.forename: Koji
authors.initials: K
authors.lastname: Ito
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Honda
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000503:physiopathology; D001794:Blood Pressure; D001933:Brain Stem / Q000378:metabolism; D006321:Heart / Q000503:physiopathology; D006333:Heart Failure / Q000503:physiopathology*; D006439:Hemodynamics; D017379:Hypertrophy, Left Ventricular; D008297:Male; D020890:Neuregulin-1 / Q000378:metabolism*; D009638:Norepinephrine / Q000652:urine; D018739:Oncogene Proteins v-erbB / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY; D015398:Signal Transduction; D013564:Sympathetic Nervous System; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology
chemical_list: D020890:Neuregulin-1; C490580:Nrg1 protein, rat; D018739:Oncogene Proteins v-erbB; D009638:Norepinephrine