Heart failure causes cholinergic transdifferentiation of cardiac sympathetic nerves via gp130-signaling cytokines in rodents.
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.
Kanazawa
Hideaki
H
Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Ieda
Masaki
M
Kimura
Kensuke
K
Arai
Takahide
T
Kawaguchi-Manabe
Haruko
H
Matsuhashi
Tomohiro
T
Endo
Jin
J
Sano
Motoaki
M
Kawakami
Takashi
T
Kimura
Tokuhiro
T
Monkawa
Toshiaki
T
Hayashi
Matsuhiko
M
Iwanami
Akio
A
Okano
Hideyuki
H
Okada
Yasunori
Y
Ishibashi-Ueda
Hatsue
H
Ogawa
Satoshi
S
Fukuda
Keiichi
K
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
D003911:Dextrans; D026901:Membrane Transport Proteins; C076397:biotinylated dextran amine; C065637:choline transporter; D001710:Biotin; D014446:Tyrosine 3-Monooxygenase; D009638:Norepinephrine