title: Heart failure causes cholinergic transdifferentiation of cardiac sympathetic nerves via gp130-signaling cytokines in rodents.
abstract: Although several cytokines and neurotrophic factors induce sympathetic neurons to transdifferentiate into cholinergic neurons in vitro, the physiological and pathophysiological roles of this remain unknown. During congestive heart failure (CHF), sympathetic neural tone is upregulated, but there is a paradoxical reduction in norepinephrine synthesis and reuptake in the cardiac sympathetic nervous system (SNS). Here we examined whether cholinergic transdifferentiation can occur in the cardiac SNS in rodent models of CHF and investigated the underlying molecular mechanism(s) using genetically modified mice. We used Dahl salt-sensitive rats to model CHF and found that, upon CHF induction, the cardiac SNS clearly acquired cholinergic characteristics. Of the various cholinergic differentiation factors, leukemia inhibitory factor (LIF) and cardiotrophin-1 were strongly upregulated in the ventricles of rats with CHF. Further, LIF and cardiotrophin-1 secreted from cultured failing rat cardiomyocytes induced cholinergic transdifferentiation in cultured sympathetic neurons, and this process was reversed by siRNAs targeting Lif and cardiotrophin-1. Consistent with the data in rats, heart-specific overexpression of LIF in mice caused cholinergic transdifferentiation in the cardiac SNS. Further, SNS-specific targeting of the gene encoding the gp130 subunit of the receptor for LIF and cardiotrophin-1 in mice prevented CHF-induced cholinergic transdifferentiation. Cholinergic transdifferentiation was also observed in the cardiac SNS of autopsied patients with CHF. Thus, CHF causes target-dependent cholinergic transdifferentiation of the cardiac SNS via gp130-signaling cytokines secreted from the failing myocardium.
authors.affiliation: Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kanazawa
authors.forename: Masaki
authors.initials: M
authors.lastname: Ieda
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kimura
authors.forename: Takahide
authors.initials: T
authors.lastname: Arai
authors.forename: Haruko
authors.initials: H
authors.lastname: Kawaguchi-Manabe
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsuhashi
authors.forename: Jin
authors.initials: J
authors.lastname: Endo
authors.forename: Motoaki
authors.initials: M
authors.lastname: Sano
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawakami
authors.forename: Tokuhiro
authors.initials: T
authors.lastname: Kimura
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Monkawa
authors.forename: Matsuhiko
authors.initials: M
authors.lastname: Hayashi
authors.forename: Akio
authors.initials: A
authors.lastname: Iwanami
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Okada
authors.forename: Hatsue
authors.initials: H
authors.lastname: Ishibashi-Ueda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
mesh_terms: D000818:Animals; D001710:Biotin / Q000031:analogs & derivatives / Q000494:pharmacology; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D003911:Dextrans / Q000494:pharmacology; D006329:Heart Conduction System / Q000503:physiopathology*; D006333:Heart Failure / Q000503:physiopathology*; D006352:Heart Ventricles / Q000294:innervation / Q000503:physiopathology; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology; D009412:Nerve Fibers / Q000502:physiology; D009474:Neurons / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D013233:Stellate Ganglion / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D013564:Sympathetic Nervous System / Q000166:cytology / Q000473:pathology / Q000503:physiopathology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D003911:Dextrans; D026901:Membrane Transport Proteins; C076397:biotinylated dextran amine; C065637:choline transporter; D001710:Biotin; D014446:Tyrosine 3-Monooxygenase; D009638:Norepinephrine