Icosapent ethyl reduces arterial thrombosis by inhibition of cyclooxygenase-1–induced platelet reactivity

作者：Philipp Mourikis, Marcel Benkhoff, Laura Wildeis, Maike Barcik, Carolin Helten, Cristina Coman, Fiorella A. Solari, D. Krahn, Lisa Dannenberg, Samantha Ahlbrecht, Dorothee Zikeli, Amelie Utz, Kajetan Trojovsky, Hannah J. Richter, Gabrielle Al Kassis, René M’Pembele, Saif Zako, Tim Huckenbeck, Sofía Bauer, Danny Schmitz, Susanne Pfeiler, Norbert Gerdes, Christof Dücker, Joachim Pircher, Zhe Zhang, Manuela Thienel, Qurrat Ul Ain, Petra Keul, Nicholas S. Kirkby, Dennis Sohn, Wilfried Budach, Thomas Hohlfeld, Karsten Schrör, Bodo Levkau, Tobias Zeus, Steven H. L. Verhelst, Robert Ahrends, Albert Sickmann, Jane A. Mitchell, Samia Mora, JoAnn E. Manson, Deepak L. Bhatt, Ulf Landmesser, Steffen Maßberg, Malte Kelm, Tobias Petzold, Amin Polzin · 发表于：Science Translational Medicine · 年份：2025 · DOI：10.1126/scitranslmed.ado0610 · 被引用次数：12 · 研究领域：Fatty Acid Research and Health、Natural Products and Biological Research、Eicosanoids and Hypertension Pharmacology

Large, randomized trials testing omega-3 polyunsaturated fatty acid (ω-3 PUFA) supplementation to reduce cardiovascular events have reported contradictory results. Interpretation of these trials is challenging, because different dosages and formulations of ω-3 PUFA were tested. Furthermore, the exact mechanisms for the reduction in cardiovascular events are unclear. In this study, we investigated the effects of ω-3 PUFA on platelet adhesion, degranulation, and aggregation in vitro and in patients with cardiovascular disease using different formulations of ω-3 PUFA. We also investigated the effects of ω-3 PUFA in rodent models of arterial thrombosis and in tail bleeding assays, including in cyclooxygenase-1 (COX-1)-deficient animals. The ω-3 PUFA eicosapentaenoic acid (EPA) dose-dependently reduced platelet adhesion, degranulation, and aggregation in vitro. Moreover, arterial thrombus formation in wild-type mice was inhibited by oral EPA administration before thrombus formation. Photoaffinity labeling and in silico docking analyses suggested a direct, competitive interaction of EPA and arachidonic acid at the level of COX-1. The COX-1 dependency of EPA's inhibitory effects was confirmed by platelet-specific COX-1-deficient animals that had no reduction of thrombus burden by EPA. In patients with cardiovascular disease, switching from 2 grams of EPA twice daily to 1 gram of docosahexaenoic acid (DHA) (460 milligrams of EPA and 380 milligrams of DHA) once daily completely blunte...