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. IntroductionCardiac function is tightly controlled by the balance between the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS). The SNS produces norepinephrine (NE) and increases the heart rate, conduction velocity, and myocardial contraction and relaxation, while the PNS produces acetylcholine (Ach) that reduces cardiac performance. In congestive heart failure (CHF), sympathetic neural tone is upregulated, and excess SNS activation leads to pathophysiological effects, such as myocardial damage, decline of cardiac function, and lethal arrhythmia (1, 2), and also causes depletion of cardiac NE content (3). This depletion of NE in CHF has been considered to be the result of excess NE secretion, disturbance of NE reuptake, and loss of noradrenergic nerve terminals (4, 5). However, we recently reported that the attenuation of NE in CHF was caused by downregulation of NE synthesis, concomitant with the reduced NE reuptake (6). However, the molecular mechanisms underlying the reduction in catecholaminergic characteristics of cardiac SNS in CHF remain poorly understood.

Dopamine stabilizes tumor blood vessels by up-regulating angiopoietin 1 expression in pericytes and Krüppel-like factor-2 expression in tumor endothelial cells

“…Using confocal microscopy, we observed the absence of tyrosine hydroxylase, a well-established marker of sympathetic nerves, in tumor blood vessels visualized by injecting FITC-lectin to the tumor-bearing animals (Fig. 1A); this finding indicates the absence of sympathetic nerves in the blood vessels of these tumors (23)(24)(25)(26). Then, to determine the effect of sympathectomy on the status of DA in these tumor tissues, we measured the concentration of DA in tumor tissues by HLPC with electrochemical detection (27).…”

Autonomic regulation therapy to enhance myocardial function in heart failure patients: the ANTHEM‐HFpEF study

“…Whether enhancing parasympathetic tone by VNS may be beneficial in patients with HFpEF and HFmrEF has not been examined. However, existing pre‐clinical and clinical evidence is available, demonstrating that sympathoinhibition using parasympathetic interventions leads to improvements in central and peripheral neural network functions, baroreceptor reflexes, myocyte energetics, and regression of LV hypertrophy 15, 17, 30, 31…”

“…Muscarinic receptor activation at the level of the cardiac myocyte reduces oxidative stress, increases contractile function, improves calcium signalling function in the heart, and normalizes gene expression 15, 16. At the same time, cholinergic trans‐differentiation of sympathetic neurons takes place, providing a protective role against sympathetically mediated pathogenesis 17. In canine and guinea pig models of hypertension‐mediated HF, chronic VNS was shown to mitigate hypertrophy and reverse multiple adverse changes in autonomic control of the heart, including myocyte size and LV mass, findings that are particularly relevant to HFpEF 18, 19…”

β2-Adrenergic and M2-muscarinic receptors decrease basal t-tubular L-type Ca2+ channel activity and suppress ventricular contractility in heart failure

“…It is somewhat surprising that acetylcholine acting on M2-muscarinic receptors worsens heart failure because many experimental studies have demonstrated that vagal stimulation has beneficial effects on heart failure (Kishi, 2012). Recently, Kanazawa et al reported that the cardiac sympathetic nervous system exhibits cholinergic transdifferentiation in heart failure (Kanazawa et al, 2010). Thus, one possibility is that such aberrant acetylcholine might cause deteriorating effects on failing cardiac myocytes.…”