Oxytocin attenuates sympathetic innervation with inhibition of cardiac mast cell degranulation in rats post myocardial infarction

Abstract

Abstract Aims: Sympathetic nerve hyperinnervation is the primary cause of fatal ventricular arrhythmia (VAs) following myocardial infarction (MI). Cardiac mast cells cause arrhythmias directly via degranulation. However, the role and mechanism of mast cell degranulation in sympathetic remodeling remain unknown. We investigated the role and mechanism of oxytocin (OT) in stabilizing cardiac mast cells and ameliorating sympathetic innervation. Methods and Results: MI was induced by coronary artery ligation. Western blotting, immunofluorescence staining, and toluidine staining of mast cells were performed to detect target protein expression levels and locations. Mast cells accumulated significantly in peri-infarcted tissues and were presentin a degranulated state. Mast cells expressed OTR, and OT infusion reduced the number of degranulated cardiac mast cellspost-MI. Eventually, sympathetic hyperinnervation was blunted as assessed by immunofluorescence for tyrosine hydroxylase (TH). Seven days post MI, the arrhythmia score of programmed electric stimulation in vehicle-treated rats with MI was higher than that in rats treated with OT. An in vitro study showed that OT stabilized mast cells via the PI3K/AKT signaling pathway. Further in vivo studies on OT deficiency mice showed worsening mast cell degranulation and sympathetic innervation on the opposite side. Conclusions: OT pretreatment inhibited the degranulation of cardiac mast cells post MI and prevented sympathetic hyperinnervation by stabilizing mast cells via the PI3K/AKT signaling pathway.