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Our previous reports have revealed that apelin exacerbates atherosclerotic lesions. However, the relationship between the elabela\u2010apelin\/APJ system and platelet aggregation and atherothrombosis is unclear. The results of the present study demonstrate that elabela and other endogenous ligands such as apelin\u201012, \u201017, and \u201036 induce platelet aggregation and thrombosis by activating the pannexin1(PANX1)\u2010P2X7 signaling pathway. Interestingly, the diuretic, spironolactone, a novel PANX1 inhibitor, alleviated elabela\u2010 and apelin isoforms\u2010induced platelet aggregation and thrombosis. Significantly, two potential antithrombotic drugs were screened out by targeting APJ receptors, including the anti\u2010HIV ancillary drug cobicistat and the traditional Chinese medicine monomer Schisandrin A. Both cobicistat and Schisandrin A abolished the effects of elabela and apelin isoforms on platelet aggregation, thrombosis, and cerebral infarction. In addition, cobicistat significantly attenuated thrombosis in a ponatinib\u2010induced zebrafish trunk model. Overall, the elabela\u2013apelin\/APJ axis mediated platelet aggregation and thrombosis via the PANX1\u2010P2X7 signaling pathway in vitro and in vivo. Blocking the APJ receptor with cobicistat\/Schisandrin A or inhibiting PANX1 with spironolactone may provide novel therapeutic strategies against thrombosis.<\/jats:p>","DOI":"10.1002\/jcb.30392","type":"journal-article","created":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T09:14:57Z","timestamp":1677662097000},"page":"586-605","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Elabela\u2010apelin\u201012, 17, 36\/APJ system promotes platelet aggregation and thrombosis via activating the PANX1\u2010P2X7 signaling pathway"],"prefix":"10.1002","volume":"124","author":[{"given":"Zhe","family":"Chen","sequence":"first","affiliation":[{"name":"Hunan Provincial Key Laboratory of tumor microenvironment responsive drug research, Hengyang Medical School, Institute of Pharmacy and Pharmacology,\u00a0Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study University of South China Hengyang 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