{"doi":"10.1002/prp2.1056","title":"Fatty acids negatively regulate platelet function through formation of noncanonical 15‐lipoxygenase‐derived eicosanoids","abstract":"The antiplatelet effect of polyunsaturated fatty acids is primarily attributed to its metabolism to bioactive metabolites by oxygenases, such as lipoxygenases (LOX). Platelets have demonstrated the ability to generate 15-LOX-derived metabolites (15-oxylipins); however, whether 15-LOX is in the platelet or is required for the formation of 15-oxylipins remains unclear. This study seeks to elucidate whether 15-LOX is required for the formation of 15-oxylipins in the platelet and determine their mechanistic effects on platelet reactivity. In this study, 15-HETrE, 15-HETE, and 15-HEPE attenuated collagen-induced platelet aggregation, and 15-HETrE inhibited platelet aggregation induced by different agonists. The observed anti-aggregatory effect was due to the inhibition of intracellular signaling including αIIbβ3 and protein kinase C activities, calcium mobilization, and granule secretion. While 15-HETrE inhibited platelets partially through activation of peroxisome proliferator-activated receptor β (PPARβ), 15-HETE also inhibited platelets partially through activation of PPARα. 15-HETrE, 15-HETE, or 15-HEPE inhibited 12-LOX in vitro, with arachidonic acid as the substrate. Additionally, a 15-oxylipin-dependent attenuation of 12-HETE level was observed in platelets following ex vivo treatment with 15-HETrE, 15-HETE, or 15-HEPE. Platelets treated with DGLA formed 15-HETrE and collagen-induced platelet aggregation was attenuated only in the presence of ML355 or aspirin, but not in the presence of 15-LOX-1 or 15-LOX-2 inhibitors. Expression of 15-LOX-1, but not 15-LOX-2, was decreased in leukocyte-depleted platelets compared to non-depleted platelets. Taken together, these findings suggest that 15-oxylipins regulate platelet reactivity; however, platelet expression of 15-LOX-1 is low, suggesting that 15-oxylipins may be formed in the platelet through a 15-LOX-independent pathway.","journal":"Pharmacology Research & Perspectives","year":2023,"id":357585,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9527,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":929214,"name":"Christopher van Hoorebeke","orcid":null,"position":1,"is_corresponding":false},{"id":329816,"name":"Benjamin E. Tourdot","orcid":"0000-0002-1701-4041","position":2,"is_corresponding":false},{"id":329814,"name":"Steve Perry","orcid":"0000-0003-4428-5338","position":3,"is_corresponding":false},{"id":297692,"name":"Grace Lee","orcid":"0000-0001-7892-2871","position":4,"is_corresponding":false},{"id":879901,"name":"Nicole Rhoads","orcid":"0000-0001-8331-5136","position":5,"is_corresponding":false},{"id":1066967,"name":"Andrew Rickenberg","orcid":"0009-0003-4367-1461","position":6,"is_corresponding":false},{"id":1107862,"name":"Abigail R. Green","orcid":null,"position":7,"is_corresponding":false},{"id":374072,"name":"James T. Sorrentino","orcid":"0000-0002-7058-9987","position":8,"is_corresponding":false},{"id":277610,"name":"Jennifer Yeung","orcid":"0000-0001-5279-025X","position":9,"is_corresponding":false},{"id":329818,"name":"John C. Freedman","orcid":"0000-0002-8779-2914","position":10,"is_corresponding":false},{"id":329819,"name":"Theodore R. Holman","orcid":"0000-0001-8072-2959","position":11,"is_corresponding":false},{"id":277616,"name":"Michael Holinstat","orcid":"0000-0001-5100-1933","position":12,"is_corresponding":false},{"id":408177,"name":"Adriana Yamaguchi","orcid":null,"position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":null,"created_at":"2026-07-19T01:13:39.186262Z","pmid":"36708179","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}