{"doi":"10.1101/2025.05.22.655387","title":"Endothelial c-IAP2 Loss Amplifies P2X7 Receptor-Driven Inflammation and Worsens Infection-Associated Pulmonary Hypertension","abstract":"ABSTRACT Schistosomiasis-associated Pulmonary Hypertension (Sch-PH) is the most common form of group I PH worldwide. Recently, data revealed that the preclinical animal model of Sch-PH exhibited gut and lung microbiome dysbiosis linked to significant endothelial dysfunction and microvascular apoptosis, but the role of pro/anti-apoptosis sensors, such as the inhibitor of apoptosis protein 2 (c-IAP2) and purinergic receptor P2X7 (P2X7R), remained unclear. Using a novel Cdh5cre-ER T2 ;cIAP1 -/- ;cIAP2 fl/fl animal model, this study investigated the contribution of endothelial c-IAP2 in this process, revealing P2X7R overexpression as a putative target in the onset of Sch-PH. Pharmacologically, inhibition of P2X7R function confirmed its role in promoting lung endothelial death and disease progression. Moreover, data suggest that microbiome-associated metabolic alterations in Sch-PH seem linked to microvascular endothelial apoptosis driven by ATP/P2X7R overactivation and suppressed c-IAP2 expression. Indeed, genetic ablation of endothelial c-IAP2 expression was sufficient to induce PH-like features in mice, with echocardiography indicating a higher pulmonary acceleration time (PAT), PAT/pulmonary ejection time (PET), and right ventricular free wall thickness after IP/IV-Egg challenge compared to controls. These findings suggest a significant contribution of lung endothelial P2X7R activation and c-IAP2 suppression to Sch-PH pathology, highlighting them as promising novel therapeutic targets for this life-threatening illness.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":558032,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1067455,"name":"Ygor Marinho","orcid":"0000-0002-4096-9735","position":1,"is_corresponding":false},{"id":1458484,"name":"Omar Loya","orcid":null,"position":2,"is_corresponding":false},{"id":494246,"name":"Samuel Yaw Aboagye","orcid":"0000-0001-7702-982X","position":3,"is_corresponding":false},{"id":1458485,"name":"DL Williams","orcid":null,"position":4,"is_corresponding":false},{"id":255752,"name":"Jun Sun","orcid":"0000-0001-7465-3133","position":5,"is_corresponding":false},{"id":228050,"name":"Serpil C. Erzurum","orcid":"0000-0001-5202-9065","position":6,"is_corresponding":false},{"id":392738,"name":"Vinicio de Jesús Pérez","orcid":"0000-0001-5532-8247","position":7,"is_corresponding":false},{"id":487874,"name":"Suellen D. Oliveira","orcid":"0000-0002-7654-1909","position":8,"is_corresponding":false},{"id":1458043,"name":"E. Villarreal","orcid":"0009-0004-5770-2625","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:55:21.727661Z","pmid":"40502111","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":[]}