Abstract 1379: Heart Failure Causes Cholinergic Differentiation of Cardiac Sympathetic Nerves Through Paracrine Secreted Factors
Background: Congestive heart failure (CHF) is characterized by activation of the sympathetic nervous system (SNS) with depletion of catecholamine stores. This depletion of NE had been considered to be caused by excess NE secretion and loss of noradrenergic nerve terminals, but recent studies reported that it was caused by the down regulation of NE synthesis and reuptake. In contrast, sympathetic neurons can transdifferentiate into cholinergic neurons (neurotransmitter switching) in sweat glands during development via LIF/gp130 pathway. The present study investigated whether this neurotransmitter switching to the cholinergic phenotype may underlie the development of CHF in adults.
Methods & Results:
Dahl salt-sensitive (DS) rats and salt-resistant (DR) rats were fed a high salt (8% NaCl) diet for 9 weeks. DS rats showed CHF.
Anti-tyrosine hydroxylase (TH, sympathetic nerve marker) immunostaining revealed that TH+ neurons were reduced in the heart and stellate ganglia of DS rats, but not in DR.
Anti-choline transporter (CHT) and anti-choline acetyltransferase (ChAT,) immunostaining, which are characteristic markers for cholinergic neurons, were performed.
CHT+ nerve fibers were markedly increased in DS rat hearts, but not in DR. ChAT+ neuronal bodies were significantly increased in the stellate ganglia of DS. (4) Next, to confirm that the cardiac SNS in DS rat failing heart undergoes cholinergic transdifferentiation, we labeled the cardiac SNS anterogradely from the stellate ganglia to the heart by injection of biotinylated dextran amines (BDA, an anterograde neuronal tracer). CHT+ nerves merged with the nerve that was labeled with BDA, indicating that the anatomical SNS obtained a cholinergic property. (5) In DS rat heart the expression of LIF and cardiotrophin-1 gradually increased concomitant with the progression of CHF. (6) We generated several transgenic mice lines that overexpressed LIF in the heart; they expressed LIF in a variety of levels. They represented cholinergic differentiation in cardiac SNS in a LIF dose-dependent manner.
Conclusions: We demonstrated that the cardiac SNS switches the neurotransmitter from a catecholaminergic to cholinergic property, mediated by cytokines secreted from failing heart.