Heart failure causes cholinergic transdifferentiation of cardiac sympathetic nerves via gp130-signaling cytokines in rodents
Hideaki Kanazawa, … , Satoshi Ogawa, Keiichi Fukuda
Hideaki Kanazawa, … , Satoshi Ogawa, Keiichi Fukuda
Published January 4, 2010
Citation Information: J Clin Invest. 2010;120(2):408-421. https://doi.org/10.1172/JCI39778.
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Research Article Cardiology

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

Hideaki Kanazawa, Masaki Ieda, Kensuke Kimura, Takahide Arai, Haruko Kawaguchi-Manabe, Tomohiro Matsuhashi, Jin Endo, Motoaki Sano, Takashi Kawakami, Tokuhiro Kimura, Toshiaki Monkawa, Matsuhiko Hayashi, Akio Iwanami, Hideyuki Okano, Yasunori Okada, Hatsue Ishibashi-Ueda, Satoshi Ogawa, Keiichi Fukuda

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Figure 1

Distribution of sympathetic and parasympathetic nerves in the rat heart.

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Distribution of sympathetic and parasympathetic nerves in the rat heart....
(A) Immunofluorescence staining for TH, CHT (green), and α-actinin (red) in the rat LV. TH+ nerves were more abundant in the subepicardial layer (epi) than the subendocardial layer (endo). The arrow indicates sympathetic nerves at the epicardial surface. No CHT+ nerves were observed at the epicardial surface, and CHT+ nerves were more abundant in the subendocardial layer. Higher-magnification views of the boxed regions are shown in the insets. (B) Quantitative analysis of TH+ nerve area of LVs (n = 5). (C) Quantitative analysis of CHT+ nerve area of LVs (n = 5). (D) Representative immunostaining for TH (red), ChAT (green), and Toto3 (blue) in rat stellate ganglia and cardiac ganglia. A ChAT+ neuron (arrow, top row) was surrounded by TH+ neurons in the stellate ganglia. A few TH+ cells (arrow, bottom row) were observed in cardiac ganglia. Higher-magnification views of the boxed regions in the third column are shown in the fourth column. Representative data are shown in each panel. *P < 0.01. Scale bars: 100 μm (A); 50 μm (A, insets, and D).