{"doi":"10.1101/2024.02.17.580812","title":"Inhibition of Soluble Epoxide Hydrolase Reduces Inflammation and Myocardial Injury in Arrhythmogenic Cardiomyopathy","abstract":"Previous studies have implicated persistent innate immune signaling in the pathogenesis of arrhythmogenic cardiomyopathy (ACM), a familial non-ischemic heart muscle disease characterized by life-threatening arrhythmias and progressive myocardial injury. Here, we provide new evidence implicating inflammatory lipid autocoids in ACM. We show that specialized pro-resolving lipid mediators are reduced in hearts of Dsg2mut/mut mice, a well characterized mouse model of ACM. We also found that ACM disease features can be reversed in rat ventricular myocytes expressing mutant JUP by the pro-resolving epoxy fatty acid (EpFA) 14,15-eicosatrienoic acid (14-15-EET), whereas 14,15-EE-5(Z)E which antagonizes actions of the putative 14,15-EET receptor, intensified nuclear accumulation of the desmosomal protein plakoglobin. Soluble epoxide hydrolase (sEH), an enzyme that rapidly converts pro-resolving EpFAs into polar, far less active or even pro-inflammatory diols, is highly expressed in cardiac myocytes in Dsg2mut/mut mice. Inhibition of sEH prevented progression of myocardial injury in Dsg2mut/mut mice and led to recovery of contractile function. This was associated with reduced myocardial expression of genes involved in the innate immune response and fewer pro-inflammatory macrophages expressing CCR2, which mediate myocardial injury in Dsg2mut/mut mice. These results suggest that pro-inflammatory eicosanoids contribute to the pathogenesis of ACM and, further, that inhibition of sEH may be an effective, mechanism-based therapy for ACM patients.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":487954,"datarank":0.19147242745358484,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.026680584153368374,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.026680584153368374,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":2,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9494,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":156032,"name":"Abigail Kelly","orcid":null,"position":1,"is_corresponding":false},{"id":259950,"name":"Weicang Wang","orcid":"0000-0002-2722-507X","position":2,"is_corresponding":false},{"id":291088,"name":"Jun Yang","orcid":"0000-0001-8126-1728","position":3,"is_corresponding":false},{"id":560455,"name":"Sung Hee Hwang","orcid":"0000-0002-9891-928X","position":4,"is_corresponding":false},{"id":1332795,"name":"Michael Allen Gillespie","orcid":null,"position":5,"is_corresponding":false},{"id":1247049,"name":"Isabella Howard","orcid":"0000-0001-8292-4693","position":6,"is_corresponding":false},{"id":640145,"name":"Carlos Bueno‐Betí","orcid":"0000-0003-4626-1276","position":7,"is_corresponding":false},{"id":640144,"name":"Angeliki Asimaki","orcid":"0000-0001-9886-6870","position":8,"is_corresponding":false},{"id":552523,"name":"Vinay Penna","orcid":"0000-0002-9082-7874","position":9,"is_corresponding":false},{"id":247530,"name":"Kory J. Lavine","orcid":"0000-0003-1948-9945","position":10,"is_corresponding":false},{"id":323202,"name":"Matthew L. Edin","orcid":"0000-0002-7042-500X","position":11,"is_corresponding":false},{"id":247404,"name":"Darryl C. Zeldin","orcid":"0000-0002-2087-7307","position":12,"is_corresponding":false},{"id":242185,"name":"Bruce D. Hammock","orcid":"0000-0003-1408-8317","position":13,"is_corresponding":false},{"id":640146,"name":"Jeffrey E. Saffitz","orcid":"0000-0001-8568-9457","position":14,"is_corresponding":false},{"id":242179,"name":"Dipak Panigrahy","orcid":"0009-0007-2302-0919","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:08:15.008850Z","pmid":"38463975","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":[]}