Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
Department of Cardiovascular Diseases, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
Neurosci Bull. 2021 May;37(5):641-656. doi: 10.1007/s12264-021-00641-8. Epub 2021 Feb 23.
The present study was designed to investigate the mechanisms by which P2X7 receptors (P2X7Rs) mediate the activation of vasopressinergic neurons thereby increasing sympathetic hyperactivity in the paraventricular nucleus (PVN) of the hypothalamus of rats with acute myocardial ischemia (AMI). The left anterior descending branch of the coronary artery was ligated to induce AMI in rats. The rats were pretreated with BBG (brilliant blue G, a P2X7R antagonist), nelivaptan (a vasopressin V1b receptor antagonist), or diphenyleneiodonium (DPI) [an nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor]. Hemodynamic parameters of the heart were monitored. Myocardial injury and cardiomyocyte apoptosis were assessed. In the PVN of AMI rats, P2X7R mediated microglial activation, while reactive oxygen species (ROS) and NADPH oxidase 2 (NOX2) were higher than in the sham group. Intraperitoneal injection of BBG effectively reduced ROS production and vasopressin expression in the PVN of AMI rats. Moreover, both BBG and DPI pretreatment effectively reduced sympathetic hyperactivity and ameliorated AMI injury, as represented by reduced inflammation and apoptosis of cardiomyocytes. Furthermore, microinjection of nelivaptan into the PVN improved cardiac function and reduced the norepinephrine (AE) levels in AMI rats. Collectively, the results suggest that, within the PVN of AMI rats, P2X7R upregulation mediates microglial activation and the overproduction of ROS, which in turn activates vasopressinergic neuron-V1b receptors and sympathetic hyperactivity, hence aggravating myocardial injury in the AMI setting.
本研究旨在探讨嘌呤能 P2X7 受体（P2X7Rs）在介导血管加压素能神经元激活中的作用机制，从而增加急性心肌缺血（AMI）大鼠下丘脑室旁核（PVN）中的交感神经活性过度。结扎冠状动脉左前降支以诱导大鼠 AMI。用 BBG（亮蓝 G，P2X7R 拮抗剂）、nelivaptan（血管加压素 V1b 受体拮抗剂）或二苯并碘（DPI）[烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶抑制剂]预处理大鼠。监测心脏的血流动力学参数。评估心肌损伤和心肌细胞凋亡。在 AMI 大鼠的 PVN 中，P2X7R 介导小胶质细胞激活，而活性氧（ROS）和 NADPH 氧化酶 2（NOX2）的水平高于假手术组。腹腔内注射 BBG 可有效减少 AMI 大鼠 PVN 中 ROS 的产生和血管加压素的表达。此外，BBG 和 DPI 预处理均可有效降低交感神经活性，改善 AMI 损伤，表现为减少心肌细胞炎症和凋亡。此外，将 nelivaptan 微注射到 PVN 可改善 AMI 大鼠的心脏功能并降低去甲肾上腺素（AE）水平。综上所述，结果表明，在 AMI 大鼠的 PVN 中，P2X7R 的上调介导小胶质细胞激活和 ROS 的过度产生，进而激活血管加压素能神经元-V1b 受体和交感神经活性过度，从而加重 AMI 中的心肌损伤。
