{"doi":"10.1111/bph.15492","title":"Olinciguat, a stimulator of soluble guanylyl cyclase, attenuates inflammation, vaso‐occlusion and nephropathy in mouse models of sickle cell disease","abstract":"BACKGROUND AND PURPOSE: Reduced bioavailability of NO, a hallmark of sickle cell disease (SCD), contributes to intravascular inflammation, vasoconstriction, vaso-occlusion and organ damage observed in SCD patients. Soluble guanylyl cyclase (sGC) catalyses synthesis of cGMP in response to NO. cGMP-amplifying agents, including NO donors and phosphodiesterase 9 inhibitors, alleviate TNFα-induced inflammation in wild-type C57BL/6 mice and in 'humanised' mouse models of SCD. EXPERIMENTAL APPROACH: Effects of the sGC stimulator olinciguat on intravascular inflammation and renal injury were studied in acute (C57BL6 and Berkeley mice) and chronic (Townes mice) mouse models of TNFα-induced and systemic inflammation associated with SCD. KEY RESULTS: Acute treatment with olinciguat attenuated increases in plasma biomarkers of endothelial cell activation and leukocyte-endothelial cell interactions in TNFα-challenged mice. Co-treatment with hydroxyurea, an FDA-approved SCD therapeutic agent, further augmented the anti-inflammatory effect of olinciguat. In the Berkeley mouse model of TNFα-induced vaso-occlusive crisis, a single dose of olinciguat attenuated leukocyte-endothelial cell interactions, improved blood flow and prolonged survival time compared to vehicle-treated mice. In Townes SCD mice, plasma biomarkers of inflammation and endothelial cell activation were lower in olinciguat- than in vehicle-treated mice. In addition, kidney mass, water consumption, 24-h urine excretion, plasma levels of cystatin C and urinary excretion of N-acetyl-β-d-glucosaminidase and neutrophil gelatinase-associated lipocalin were lower in Townes mice treated with olinciguat than in vehicle-treated mice. CONCLUSION AND IMPLICATIONS: Our results suggest that the sGC stimulator olinciguat attenuates inflammation, vaso-occlusion and kidney injury in mouse models of SCD and systemic inflammation.","journal":"British Journal of Pharmacology","year":2021,"id":172464,"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":25,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9571,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":708650,"name":"Huihui Li","orcid":"0000-0003-4608-1179","position":1,"is_corresponding":false},{"id":265875,"name":"Sung Kyun Lee","orcid":"0000-0001-8130-7431","position":2,"is_corresponding":false},{"id":708651,"name":"Xin Gao","orcid":"0000-0002-5927-2241","position":3,"is_corresponding":false},{"id":709417,"name":"Raghunath Ramanarasimhaiah","orcid":null,"position":4,"is_corresponding":false},{"id":708652,"name":"Guang Liu","orcid":"0009-0000-8582-9624","position":5,"is_corresponding":false},{"id":708653,"name":"K. Hall","orcid":"0000-0003-1091-6074","position":6,"is_corresponding":false},{"id":709418,"name":"Sylvie G. Bernier","orcid":null,"position":7,"is_corresponding":false},{"id":708654,"name":"Juli E. Jones","orcid":"0000-0002-3870-1705","position":8,"is_corresponding":false},{"id":708655,"name":"Susanne Feil","orcid":"0000-0003-2148-8773","position":9,"is_corresponding":false},{"id":708656,"name":"Robert Feil","orcid":"0000-0002-7335-4841","position":10,"is_corresponding":false},{"id":375958,"name":"Emmanuel S. Buys","orcid":"0000-0002-1763-9359","position":11,"is_corresponding":false},{"id":709419,"name":"Regina Margaret Graul","orcid":null,"position":12,"is_corresponding":false},{"id":265877,"name":"Paul S. Frenette","orcid":"0000-0003-0862-9922","position":13,"is_corresponding":false},{"id":709420,"name":"Jaime L. Masferrer","orcid":null,"position":14,"is_corresponding":false},{"id":709416,"name":"Boris Tchernychev","orcid":null,"position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-18T23:46:41.424716Z","pmid":"33864386","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":[]}