Talabieke Shaletanati, Yang Xuejian, Yang Jianfeng, Wan Qing, Zhu Dekun, Rao Haojie, Wu Yifei, Chen Zengrong, Li Huihui, Xu Pengfei, Chen Hong, Liu De-Pei, Zhang Xu, FitzGerald Garret A, Wang Miao
State Key Laboratory of Cardiovascular Disease, Clinical Pharmacology Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, 167 Beilishi Road, Xicheng District, Beijing 100037, China.
Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
Cardiovasc Res. 2025 May 23;121(5):775-787. doi: 10.1093/cvr/cvae254.
The therapeutic efficacy of coronary revascularization is compromised by myocardial ischaemia-reperfusion (MI/R) injury. Higher levels of circulating arachidonic acid (AA) are reportedly associated with lower risk of cardiovascular disease. The cyclooxygenase (COX) pathway metabolizes AA into prostaglandins (PGs) and the platelet-activating thromboxane A2 (TXA2), which is inhibited by aspirin. We aimed to explore whether AA or its combination with aspirin modulates MI/R injury and aspirin-caused gastric bleeding.
Mice were subjected to 30-min coronary artery ligation followed by reperfusion. AA reduced MI/R injury in mice, and its combination with aspirin provided further cardioprotection. Aspirin inhibited MI/R-triggered platelet activation and ameliorated microvascular obstruction immediately upon reperfusion, whereas AA improved microvascular perfusion at a later stage of reperfusion, coinciding with increased coronary vasodilatation. Co-administration of AA and aspirin markedly reduced cardiac neutrophil infiltration and vascular permeability and improved microcirculation. AA increased urinary metabolites of PGI2 and PGE2, not TXA2, and this selective augmentation was further enhanced by co-treatment with aspirin. Elevation in PGI2 and PGE2 correlated with reduced infarction and improved ventricular function, and inhibiting COX-2 attenuated the synergistic cardioprotection. Furthermore, oral administration of AA with aspirin after reperfusion provided a maximal cardioprotection and abolished aspirin-caused gastric bleeding.
AA synergizes with aspirin in protecting against MI/R injury, while minimizing the related bleeding risk, a major concern for patients with acute myocardial infarction. This is attributable to the selective augmentation of PGI2 and PGE2 that is amplified by TXA2 suppression by aspirin, underscoring improved microcirculation and ameliorated inflammation.
心肌缺血再灌注（MI/R）损伤会削弱冠状动脉血运重建的治疗效果。据报道，循环中较高水平的花生四烯酸（AA）与较低的心血管疾病风险相关。环氧合酶（COX）途径将AA代谢为前列腺素（PGs）和血小板激活的血栓素A2（TXA2），而阿司匹林可抑制该途径。我们旨在探讨AA或其与阿司匹林联合使用是否能调节MI/R损伤以及阿司匹林引起的胃出血。
对小鼠进行30分钟冠状动脉结扎，随后再灌注。AA减轻了小鼠的MI/R损伤，其与阿司匹林联合使用提供了进一步的心脏保护作用。阿司匹林抑制MI/R触发的血小板活化，并在再灌注后立即改善微血管阻塞，而AA在再灌注后期改善微血管灌注，这与冠状动脉扩张增加相吻合。AA和阿司匹林联合给药显著减少心脏中性粒细胞浸润和血管通透性，并改善微循环。AA增加了前列环素I2（PGI2）和前列腺素E2（PGE2）的尿代谢产物，而非TXA2，与阿司匹林联合治疗进一步增强了这种选择性增加。PGI2和PGE2的升高与梗死面积减小和心室功能改善相关，抑制COX-2减弱了协同心脏保护作用。此外，再灌注后口服AA与阿司匹林可提供最大程度的心脏保护，并消除阿司匹林引起的胃出血。
AA与阿司匹林协同预防MI/R损伤，同时将相关出血风险降至最低，这是急性心肌梗死患者的主要担忧。这归因于PGI2和PGE2的选择性增加，而阿司匹林抑制TXA2可放大这种增加，突出了微循环改善和炎症减轻。
