Arachidonic acid synergizes with aspirin preventing myocardial ischemia-reperfusion injury and mitigates bleeding risk

Shaletanati Talabieke; Xuejian Yang; Jianfeng Yang; Qing Wan; Dekun Zhu; Haojie Rao; Yifei Wu; Zengrong Chen; Huihui Li; Pengfei Xu; Hong Chen; De-Pei Liu; Xu Zhang; Garret A FitzGerald; Miao Wang

doi:10.1093/cvr/cvae254

Arachidonic acid synergizes with aspirin preventing myocardial ischemia-reperfusion injury and mitigates bleeding risk

Cardiovasc Res. 2025 Jan 9:cvae254. doi: 10.1093/cvr/cvae254. Online ahead of print.

Authors

Shaletanati Talabieke¹, Xuejian Yang¹, Jianfeng Yang¹, Qing Wan¹, Dekun Zhu¹, Haojie Rao¹, Yifei Wu¹, Zengrong Chen¹, Huihui Li¹, Pengfei Xu¹, Hong Chen¹, De-Pei Liu², Xu Zhang³, Garret A FitzGerald⁴, Miao Wang^{1

5}

Affiliations

¹ State Key Laboratory of Cardiovascular Disease, Clinical Pharmacology Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
² State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China.
³ Tianjin Key Laboratory of Metabolic Diseases, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Center for Cardiovascular Diseases, Research Center of Basic Medical Sciences, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300070, China.
⁴ Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ National Health Commission Cardiovascular Disease Regenerative Medicine Research Key Laboratory, Central China Subcenter of National Center for Cardiovascular Diseases, Henan Cardiovascular Disease Center, Fuwai Central-China Cardiovascular Hospital, Central China Fuwai Hospital of Zhengzhou University. Zhengzhou 450046, China.

PMID: 39780702
DOI: 10.1093/cvr/cvae254

Abstract

Aims: The therapeutic efficacy of coronary revascularization is compromised by myocardial ischemia-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.

Methods and results: Mice were subjected to 30min 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 cadioprotection. Furthermore, oral administration of AA with aspirin after reperfusion provided a maximal cardioprotection and abolished aspirin-caused gastric bleeding.

Conclusion: 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.

Keywords: arachidonic acid; aspirin; myocardial ischemia-reperfusion; prostanoid.

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