Hypoxia-inducible factor-1α attenuates myocardial inflammatory injury in rats induced by coronary microembolization

Abstract To investigated the role of HIF-1α in myocardial inflammatory injury in rats induced by CME and its possible mechanism. Forty SD rats were separated randomly and equally into four groups, i.e. CME+HIF-1α stabilizer dimethyloxalyl glycine (CME+DMOG) group, CME+HIF-1α inhibitor YC-1 (CME+YC-1) group, CME group, and Sham group. HBFP staining, myocardial enzyme assessment, and cardiac ultrasound were used to measure microinfarct, serum c-troponin I (cTnI) level, and Cardiac function. ELISA and western blot were applied for detecting NLRP3 inflammasome pathway and TLR4/MyD88/NF-κB signaling level.Pro-inflammatory factors of IL-18, IL-1β and TNF-α increased their expression levels after CME, which indicated inflammatory responses in the myocardium. Additionally, in the inflammatory process, NLRP3 inflammasome and TLR4/MyD88/NF-κB signaling were involved. DMOG reverses these effects of CME, whereas YC-1 aggravates these effects. HIF-1α may attenuate myocardial inflammatory injury induced by CME and improve cardiac function, which can perhaps be explained by the fact that TLR4/MyD88/NF-κB signaling pathway activation is inhibited.摘要：本研究旨在探讨缺氧诱导因子-1α（HIF-1α）在冠状微循环栓塞（CME）诱导的大鼠心肌炎性损伤中的作用及其潜在机制。将40只SD大鼠随机均分为四组，分别为CME+HIF-1α稳定剂二甲基乙二酰基甘氨酸（DMOG）组、CME+HIF-1α抑制剂YC-1（CME+YC-1）组、CME模型组与假手术（Sham）组。采用苏木精-碱性品红-苦味酸（HBFP）染色、心肌酶学检测及心脏超声分别检测微梗死灶、血清心肌肌钙蛋白I（cTnI）水平与心功能；采用酶联免疫吸附测定（ELISA）与蛋白质免疫印迹（Western Blot）检测核苷酸结合寡聚化结构域样受体蛋白3（NLRP3）炎性小体通路以及Toll样受体4（TLR4）/髓系分化因子88（MyD88）/核因子κB（NF-κB）信号通路的活化水平。结果显示，CME造模后，促炎因子白细胞介素-18（IL-18）、白细胞介素-1β（IL-1β）及肿瘤坏死因子-α（TNF-α）的表达水平均显著升高，提示心肌组织出现炎性应答反应；同时，NLRP3炎性小体与TLR4/MyD88/NF-κB信号通路均参与了该炎性进程。二甲基乙二酰基甘氨酸（DMOG）可逆转CME诱导的上述异常效应，而YC-1则会加重这些病理变化。综上，HIF-1α或可减轻CME诱导的大鼠心肌炎性损伤并改善心功能，其潜在机制可能与抑制TLR4/MyD88/NF-κB信号通路的活化有关。