Background and Aims Depression, the most prevalent psychiatric disorder, is associated with the occurrence and development of atrial fibrillation (AF). P2X7 receptor (P2X7R) activation participates in the development of depression, but little attention has been given to its role in AF. This study was to investigate the effects of P2X7R on AF in depression models. Methods Lipopolysaccharide (LPS) and chronic unpredictable stress (CUS) were carried out to induce depression in rodents. Behavioral assessments, atrial electrophysiological parameters, Electrocardiogram (ECG) parameters, western blot, and histology were performed. Results AF inducibility was increased in both LPS- and CUS-induced depression, along with the up-regulation of P2X7R in atria. CUS facilitated atrial fibrosis. CUS reduced HRV and increased the expression of TH and GAP43, representing autonomic dysfunction. Downregulation of Nav1.5, Cav1.2, Kv1.5, Kv4.3, Cx40, and Cx43 in CUS indicated the abnormalities in ion channels. In addition, the expression levels of TLR4, P65, P-P65, NLRP3, ASC, caspase-1, and IL-1β were elevated in depression models. Pharmacological inhibitor (Brilliant Blue G, BBG) or genetic deficiency of P2X7R significantly mitigated depressive-like behaviors; ameliorated electrophysiological deterioration and autonomic dysfunction; improved ion channel expression and atrial fibrosis; and prevented atrial NLRP3 inflammasome activation in the pathophysiological process of AF in depression models. Conclusion LPS or CUS induces AF and promotes P2X7R-dependent activation of NLRP3 inflammasome, whereas pharmacological P2X7R inhibition or P2X7R genetic deficiency prevents atrial remodeling without interrupting normal atrial physiological functions. Our results point to P2X7R as an important factor in the pathology of AF in depression.

中文翻译：

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P2X7 受体抑制可预防抑郁症啮齿动物模型中的心房颤动

背景和目的抑郁症是最常见的精神疾病，与心房颤动（AF）的发生和发展有关。P2X7 受体 (P2X7R) 激活参与抑郁症的发生，但其在 AF 中的作用却很少受到关注。本研究旨在探讨 P2X7R 对抑郁症模型中 AF 的影响。方法采用脂多糖（LPS）和慢性不可预测应激（CUS）诱导啮齿类动物抑郁。进行行为评估、心房电生理参数、心电图（ECG）参数、蛋白质印迹和组织学。结果 LPS 和 CUS 诱导的抑郁症中 AF 诱导性均增加，同时心房中 P2X7R 的上调。CUS 促进心房纤维化。CUS 降低 HRV，增加 TH 和 GAP43 的表达，代表自主神经功能障碍。CUS 中 Nav1.5、Cav1.2、Kv1.5、Kv4.3、Cx40 和 Cx43 的下调表明离子通道异常。此外，抑郁症模型中 TLR4、P65、P-P65、NLRP3、ASC、caspase-1 和 IL-1β 的表达水平升高。药物抑制剂（Brilliant Blue G、BBG）或 P2X7R 遗传缺陷可显着减轻抑郁样行为；改善电生理恶化和自主神经功能障碍；改善离子通道表达和心房纤维化；并在抑郁模型的 AF 病理生理过程中阻止心房 NLRP3 炎性体激活。结论 LPS或CUS诱导AF并促进NLRP3炎症小体的P2X7R依赖性激活，而药理学P2X7R抑制或P2X7R遗传缺陷可防止心房重塑而不中断正常心房生理功能。我们的结果表明 P2X7R 是抑郁症 AF 病理学的重要因素。