催产素通过抑制心肌梗死后大鼠心脏肥大细胞脱颗粒来减弱交感神经支配。

Oxytocin Attenuates Sympathetic Innervation with Inhibition of Cardiac Mast Cell Degranulation in Rats after Myocardial Infarction.

作者信息

Yin Jie, Wang Ye, Han Weizhong, Ge Weili, Yu Qingxia, Jing Yanyan, Yan Wenju, Liu Qian, Gong Liping, Yan Suhua, Wang Shuanglian, Li Xiaolu, Li Yan, Hu Hesheng

机构信息

Department of Cardiology (J.Y., Y.W., S.Y., H.H.), Department of Emergency Medicine (X.L.), and Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine (Y.L.), The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China; Department of Cardiology, Shandong Provincial Hospital affiliated with Shandong First Medical University, Jinan, China (J.Y., W.H.); Department of Cardiology, Taizhou Hospital of Zhejiang Province affiliated with Wenzhou Medical University, Zhejiang, China (W.G.); School of Medicine, Shandong University, Jinan, China (Q.Y., Y.J., W.Y., Q.L.); Department of Infectious Disease and Hepatology, the Second Hospital of Shandong University, Shandong University, Jinan, China (L.G.); and Medical Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China (S.W.).

出版信息

J Pharmacol Exp Ther. 2024 Jul 18;390(2):240-249. doi: 10.1124/jpet.124.002064.

DOI:10.1124/jpet.124.002064

PMID:38902033

Abstract

Sympathetic hyperinnervation is the leading cause of fatal ventricular arrhythmia (VA) after myocardial infarction (MI). Cardiac mast cells cause arrhythmias directly through degranulation. However, the role and mechanism of mast cell degranulation in sympathetic remodeling remain unknown. We investigated the role of oxytocin (OT) in stabilizing cardiac mast cells and improving sympathetic innervation in rats. MI was induced by coronary artery ligation. Western blotting, immunofluorescence, and toluidine staining of mast cells were performed to determine the expression and location of target protein. Mast cells accumulated significantly in peri-infarcted tissues and were present in a degranulated state. They expressed OT receptor (OTR), and OT infusion reduced the number of degranulated cardiac mast cells post-MI. Sympathetic hyperinnervation was attenuated as assessed by immunofluorescence for tyrosine hydroxylase (TH). Seven days post-MI, the arrhythmia score of programmed electrical stimulation was higher in vehicle-treated rats with MI than in rats treated with OT. An in vitro study showed that OT stabilized mast cells via the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. Further in vivo studies on OTR-deficient mice showed worsening mast cell degranulation and worsening sympathetic innervation. OT pretreatment inhibited cardiac mast cell degranulation post-MI and prevented sympathetic hyperinnervation, along with mast cell stabilization via the PI3K/Akt pathway. SIGNIFICANCE STATEMENT: This is the first study to elucidate the role and mechanism of oxytocin (OT) in inflammatory-sympathetic communication mediated sympathetic hyperinnervation after myocardial infarction (MI), providing new approaches to prevent fatal arrhythmias.

摘要

交感神经去神经支配过度是心肌梗死（MI）后致命性室性心律失常（VA）的主要原因。心脏肥大细胞通过脱颗粒直接导致心律失常。然而，肥大细胞脱颗粒在交感神经重塑中的作用和机制尚不清楚。我们研究了催产素（OT）在稳定大鼠心脏肥大细胞和改善交感神经支配方面的作用。通过冠状动脉结扎诱导MI。进行肥大细胞的蛋白质印迹、免疫荧光和甲苯胺染色，以确定靶蛋白的表达和定位。肥大细胞在梗死周围组织中显著聚集，并处于脱颗粒状态。它们表达OT受体（OTR），OT输注减少了MI后脱颗粒的心脏肥大细胞数量。通过酪氨酸羟化酶（TH）的免疫荧光评估，交感神经去神经支配过度得到缓解。MI后7天，MI假手术组大鼠的程控电刺激心律失常评分高于OT治疗组大鼠。体外研究表明，OT通过磷酸肌醇3激酶/蛋白激酶B（PI3K/Akt）信号通路稳定肥大细胞。对OTR缺陷小鼠的进一步体内研究表明，肥大细胞脱颗粒和交感神经支配恶化。OT预处理抑制MI后心脏肥大细胞脱颗粒，防止交感神经去神经支配过度，并通过PI3K/Akt途径稳定肥大细胞。意义声明：这是第一项阐明催产素（OT）在心肌梗死（MI）后炎症-交感神经通讯介导的交感神经去神经支配过度中的作用和机制的研究，为预防致命性心律失常提供了新方法。