Abstract
RationaleAfter cardiac damage, excessive neurite outgrowth (sympathetic hyperinnervation) can occur, which is related to ventricular arrhythmias/sudden cardiac death. Post-damage reactivation of epicardium causes epicardium-derived cells (EPDCs) to acquire a mesenchymal character, contributing to cardiac regeneration. Whether EPDCs also contribute to cardiac re/hyperinnervation, is unknown. AimTo investigate whether mesenchymal EPDCs influence cardiac sympathetic innervation. Methods and resultsSympathetic ganglia were co-cultured with mesenchymal EPDCs and/or myocardium, and neurite outgrowth and sprouting density were assessed. Results showed a significant increase in neurite density and directional (i.e. towards myocardium) outgrowth when ganglia were co-cultured with a combination of EPDCs and myocardium, as compared to cultures with EPDCs or myocardium alone. In absence of myocardium, this outgrowth was not directional. Neurite differentiation of PC12 cells in conditioned medium confirmed these results via a paracrine effect, in accordance with expression of neurotrophic factors in myocardial explants co-cultured with EPDCs. Of interest, EPDCs increased the expression of nerve growth factor (NGF) in cultured, but not in fresh myocardium, possibly due to an “ischemic state” of cultured myocardium, supported by TUNEL and Hif1α expression. Cardiac tissues after myocardial infarction showed robust NGF expression in the infarcted, but not remote area. ConclusionNeurite outgrowth and density increases significantly in the presence of EPDCs by a paracrine effect, indicating a new role for EPDCs in the occurrence of sympathetic re/hyperinnervation after cardiac damage.
Highlights
Cardiac function is influenced by the cardiac autonomic nervous system tone
Comparison of the occurrence of neurite outgrowth between Superior cervical ganglia (SCG) in vehicle condition and in +epicardium-derived cells (EPDCs) condition demonstrated that EPDCs significantly increase the neurite outgrowth of sympathetic ganglia (Fig. 1F)
As we previously found an increase of ET-1 in reactivated mesenchymal human EPDCs (Supplemental Fig. S4C), we first examined the expression of gene Endothelin receptor A (EdnrA) in myocardium
Summary
Cardiac function is influenced by the cardiac autonomic nervous system tone. Cardiac sympathetic stimulation increases heart rate, contraction force and atrioventricular conduction velocity, whereas parasympathetic stimulation largely results in opposite effects. Balanced cardiac sympathetic and parasympathetic activity is critical for maintaining normal cardiac function. An accumulating amount of reports indicate a relation between ventricular arrhythmias, sudden cardiac death and activity of the sympathetic autonomic nervous system [3,4]. Sudden cardiac death after myocardial infarction (MI) is in general attributed to heterogeneous conduction in the infarct border zone [5], autonomic hyperinnervation after MI is related to sudden cardiac death in numerous reports [6,7]. Sympathetic hyperinnervation has been described in other states of cardiac damage/overload, such as hypertension, RV overload and pulmonary hypertension [8,9]
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