Study on the amelioration of myocardial ischemia-reperfusion injury in mice by a chemokine receptor CXC chemokine receptor-2 inhibitor
Shao Yihui
Huang Shan
Zhu Shuolin
Li Yulin
Abstract：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.
Keywords：Myocardial ischemia-reperfusion injuryCXC chemokine receptor-2 inhibitorInflammatory responseMitochondrial function
Publication Date：2025-10-18
Online Publishing Date：2026-09-14(First online date of this platform, not the publication date of the document)
Pages：4( 1470-1473 )