RRC ID 27712
Author Kanazawa H, Ieda M, Kimura K, Arai T, Kawaguchi-Manabe H, Matsuhashi T, Endo J, Sano M, Kawakami T, Kimura T, Monkawa T, Hayashi M, Iwanami A, Okano H, Okada Y, Ishibashi-Ueda H, Ogawa S, Fukuda K.
Title Heart failure causes cholinergic transdifferentiation of cardiac sympathetic nerves via gp130-signaling cytokines in rodents.
Journal J Clin Invest
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.
Volume 120(2)
Pages 408-21
Published 2010-2-1
DOI 10.1172/JCI39778
PII 39778
PMID 20051627
PMC PMC2810079
MeSH Animals Biotin / analogs & derivatives Biotin / pharmacology Cell Transdifferentiation Cells, Cultured Dextrans / pharmacology Heart Conduction System / physiopathology* Heart Failure / physiopathology* Heart Ventricles / innervation Heart Ventricles / physiopathology Membrane Transport Proteins / metabolism Mice Myocytes, Cardiac / metabolism Myocytes, Cardiac / physiology Nerve Fibers / physiology Neurons / physiology Norepinephrine / metabolism Rats Stellate Ganglion / drug effects Stellate Ganglion / physiology Stellate Ganglion / physiopathology Sympathetic Nervous System / cytology Sympathetic Nervous System / pathology Sympathetic Nervous System / physiopathology* Tyrosine 3-Monooxygenase / metabolism
IF 11.864
Times Cited 73
DNA material pCALNL5 (RDB01862)