BACKGROUND Sympathetic overactivation after acute myocardial infarction (AMI) contributes to ventricular arrhythmia (VA). Paraventricular nucleus (PVN) of the hypothalamus may play an important role on this context, however, the mechanisms remain unknown. In this study, we investigated whether inhibition of activated astrocytes in the PVN could reduce VA in rats with AMI. METHODS The anesthetized rats were randomly divided into four groups of sham-operated, AMI, AMI + vehicle and AMI + fluorocitrate (FCA). Electrocardiogram was continuously recorded. RNA sequencing, sympathetic nerve activity (heart rate variability and norepinephrine levels) and ventricular electrical instability (ventricular effective refractory period and ventricular fibrillation inducibility) were measured. Furthermore, brain tissues were extracted to detect expression of inflammatory cytokines (IL-6, and TNF-α), astrocyte and neuro activation. RESULTS RNA sequencing analysis showed that functions of differentially expressed genes in the PVN of AMI rats were significantly enriched in immune system- and neuroactive-related pathways, along with enhance expression of cytokines and Glial fibrillary acidic protein (GFAP). We further characterized that astrocytes were activated in PVN and intervention of activation astrocytes by FCA significantly inhibited sympathetic nerve activity and decreased the incidence of VA and ventricular electrical instability in rats with AMI. Moreover, FCA significantly attenuated neurons activation and downregulated expression of inflammatory cytokines in the PVN. CONCLUSIONS Inhibition of activated astrocytes in the PVN could reduce VA occurrence and improve ventricular electrical instability in AMI rats by central neuro-immune pathway. These findings suggest that astrocytes are a potential target for prevention and treatment of VA complicating AMI.

中文翻译：

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下丘脑室旁核中活化星形胶质细胞的调节，以防止导致急性心肌梗塞的室性心律不齐。

背景技术急性心肌梗死（AMI）后交感神经过度活化导致室性心律不齐（VA）。下丘脑室旁核（PVN）可能在这种情况下发挥重要作用，但是，其机制仍然未知。在这项研究中，我们调查了抑制PVN中活化的星形胶质细胞是否可以降低AMI大鼠的VA。方法将麻醉大鼠随机分为四组：假手术组，AMI组，AMI +载体组和AMI +氟柠檬酸（FCA）组。连续记录心电图。测量RNA测序，交感神经活动（心率变异性和去甲肾上腺素水平）和心室电不稳定（心室有效不应期和心室纤颤诱导性）。此外，提取脑组织以检测炎性细胞因子（IL-6和TNF-α）的表达，星形胶质细胞和神经激活。结果RNA测序分析表明，AMI大鼠PVN中差异表达基因的功能显着丰富了免疫系统和神经活性相关途径，并增强了细胞因子和神经胶质原纤维酸性蛋白（GFAP）的表达。我们进一步表征星形胶质细胞在PVN中被激活，FCA激活星形胶质细胞的干预显着抑制了AMI大鼠的交感神经活动并降低了VA的发生率和心室电不稳定。此外，FCA显着减弱了PVN中神经元的激活并下调了炎性细胞因子的表达。结论通过中枢神经免疫途径抑制PVN中活化的星形胶质细胞可以减少VA的发生并改善AMI大鼠的心室电稳定性。这些发现表明，星形胶质细胞是预防和治疗VA并发AMI的潜在靶标。