Elabela‐apelin‐12, 17, 36/APJ system promotes platelet aggregation and thrombosis via activating the PANX1‐P2X7 signaling pathway

Abstract The elabela‐apelin/angiotensin domain type 1 receptor‐associated protein (APJ) system is an important regulator in certain thrombosis‐related diseases such as atherosclerosis, myocardial infarction, and cerebral infarction. Our previous reports have revealed that apelin exacerbates atherosclerotic lesions. However, the relationship between the elabela‐apelin/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‐12, ‐17, and ‐36 induce platelet aggregation and thrombosis by activating the pannexin1(PANX1)‐P2X7 signaling pathway. Interestingly, the diuretic, spironolactone, a novel PANX1 inhibitor, alleviated elabela‐ and apelin isoforms‐induced platelet aggregation and thrombosis. Significantly, two potential antithrombotic drugs were screened out by targeting APJ receptors, including the anti‐HIV 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‐induced zebrafish trunk model. Overall, the elabela–apelin/APJ axis mediated platelet aggregation and thrombosis via the PANX1‐P2X7 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.