2025 年第 10 期 第 20 卷

CXC趋化因子受体2抑制剂改善小鼠心肌缺血再灌注损伤研究

Study on the amelioration of myocardial ischemia-reperfusion injury in mice by a chemokine receptor CXC chemokine receptor-2 inhibitor

作者：邵怡辉黄山朱硕霖李玉琳

英文作者：Shao Yihui Huang Shan Zhu Shuolin Li Yulin

单位：首都医科大学附属北京安贞医院心血管基础与转化医学中心，北京100029

英文单位：Cardiovascular Basic and Translational Medicine Center Beijing Anzhen Hospital Capital Medical University Beijing 100029 China

关键词：心肌缺血再灌注损伤；CXC趋化因子受体2抑制剂；炎症反应；线粒体功能

英文关键词：Myocardialischemia-reperfusioninjury;CXCchemokinereceptor-2inhibitor;Inflammatoryresponse;Mitochondrialfunction

• 摘要：

• 目的 探讨CXC趋化因子受体2（CXCR2）小分子抑制剂AZD5069对心肌缺血再灌注（IR）损伤（IRI）的作用及其机制。方法 采用C57BL/6小鼠建立心肌IR模型，随机分为对照组和观察组（各10只）。对照组每日灌胃0.5%羧甲基纤维素钠溶液（溶剂对照），观察组每日灌胃AZD5069 10 mg/kg，溶于0.5%羧甲基纤维素钠。另选取6只小鼠仅进行开胸操作而不结扎左冠状动脉前降支，作为假手术组。通过小动物超声心动图动态评估术后24 h、72 h及28 d的心功能指标。利用石蜡包埋心脏组织切片进行天狼星红染色以量化心肌纤维化程度。采用伊文思蓝/TTC双染色法（EB/TTC）区分心肌缺血区与非缺血区、存活区与非存活区。通过心肌组织RNA转录组测序解析AZD5069的作用机制。结果 术后24 h、72 h及28 d，观察组左心室射血分数均高于对照组［（48.0±5.5）%比（35.3±3.0）%、（55.8±5.1）%比（40.9±4.1）%、（54.9±5.4）%比（43.9±7.9）%］（均P<0.05）。IR术后28 d，观察组、对照组及假手术组心肌胶原容积分数比较差异有统计学意义（P<0.001），其中对照组高于假手术组，而观察组低于对照组（均P<0.05）。EB/TTC定量分析结果显示，观察组小鼠心肌苍白色梗死区/缺血危险区面积比值低于对照组（P＜0.05）。RNA转录组测序结果显示，AZD5069显著上调的基因主要包括CXC基序趋化因子配体1、血清淀粉样蛋白A3和Krüppel样因子2等。结论 CXCR2小分子抑制剂AZD5069可能通过抑制炎症和改善能量代谢减轻心肌IRI，为临床心肌梗死后心肌保护提供新的治疗思路。

• Objective To investigate the effect of the CXC chemokine receptor-2 (CXCR2) small-molecule inhibitor AZD5069 on myocardial ischemia-reperfusion (IR) injury (IRI) and its underlying mechanisms. Methods C57BL/6 mice were used to establish a myocardial IR model, and they were randomly divided into control group and observation group (10 mice each). The control group was given 0.5% sodium carboxymethyl cellulose solution (solvent control) daily, and the observation group was given AZD5069 10 mg/kg daily and dissolved in 0.5% sodium carboxymethyl cellulose. In addition, 6 mice were selected as the sham operation group for thoracotomy without ligation of the left anterior descending coronary artery. Cardiac function indexes were dynamically evaluated at 24 h, 72 h and 28 days after surgery by echocardiography in small animals. Sirius red staining was performed with paraffin-embedded heart tissue sections to quantify the degree of myocardial fibrosis. Evans blue/TTC double staining (EB/TTC) was used to distinguish myocardial ischemic and non-ischemic areas, and viable and non-viable areas. The mechanism of action of AZD5069 was elucidated by RNA transcriptome sequencing of myocardial tissues. Results At 24 h, 72 h and 28 days after operation, the left ventricular ejection fraction in the observation group was higher than that in the control group ［(48.0±5.5)% vs (35.3±3.0)%, (55.8±5.1)% vs (40.9±4.1)%, (54.9±5.4)% vs (43.9±7.9)%］(all P<0.05). On the 28th day after IR surgery, there was a statistically significant difference in myocardial collagen volume scores between the observation group, the control group and the sham operation group (P<0.001), and that in the control group was higher than that in the sham operation group, and that in the observation group was lower than that in the control group (both P<0.05). The results of EB/TTC quantitative analysis showed that the ratio of myocardial pale infarct area/ischemia area at risk in the observation group was lower than that in the control group (P<0.05). RNA transcriptome sequencing results showed that the genes that were significantly up-regulated AZD5069 mainly included CXC motif chemokine ligand 1, serum amyloid A3 and Krüppel-like factor 2. Conclusion The small-molecule CXCR2 antagonist AZD5069 demonstrates potential in mitigating myocardial ischemia-reperfusion injury through dual mechanisms of anti-inflammatory action and metabolic modulation, thereby proposing a novel therapeutic paradigm for post-infarction cardioprotection in clinical settings.