Abstract 3089: Heart Failure Causes Cholinergic Transdifferentiation of Cardiac Sympathetic Nerves via Gp130-mediated Cytokines
[Background] Despite upregulation of sympathetic neural tone during congestive heart failure, there is a paradoxical reduction in norepinephrine synthesis and reuptake in cardiac sympathetic nervous system. Cytokines and neurotrophic factors induce sympathetic neurons to switch neurotransmitter and transdifferentiate into cholinergic neurons in vitro and in sweat glands during development via gp130 pathway. The present study investigated whether this cholinergic transdifferentiation of the cardiac sympathetic nervous system may occur under the development of congestive heart failure.
[Methods and results] (1) We demonstrated in both an animal model (Dahl sensitive hypertensive rats) and patients with congestive heart failure, that their cardiac sympathetic nervous system clearly acquired cholinergic characteristics. (2) Anterograde labeling of cardiac sympathetic nerve fibers confirmed that these cholinergic marker positive nerves were derived from the sympathetic nervous system. (3) Among various cholinergic differentiation factors, leukemia inhibitory factor (LIF) and cardiotrophin-1 were strongly upregulated in congestive heart failure. (4) LIF and cardiotrophin-1 secreted from cultured failing cardiomyocytes induced cholinergic transdifferentiation in cultured sympathetic neurons. (5) We then specifically inhibited LIF and/or cardiotrophin-1 expression by pretreat-ment of cardiomyocytes with small interfering RNA (siRNA) before the stimulation with angiotensin II. In the siRNA treated groups, the degree of cholinergic expression was reduced relative to the untreated control cells. (6) We also confirmed that cholinergic transdifferentiation is induced by cardiac specific overexpression of LIF in mice. (7) Moreover, we found that sympathetic neuron-specific gp130 gene targeting mice can rescue the congestive heart failure-induced cholinergic transdifferentiation.
[Conclusions] We showed that cardiac sympathetic nervous system in the failing heart switched the neurotransmitter and transdifferen-tiate from catecholaminergic into cholinergic neurons and that this process was induced by gp130-mediated signaling via cholinergic differentiation factors released from the failing myocardium.