{"doi":"10.3390/cimb47110943","title":"Citrullinated and Malondialdehyde–Acetaldehyde-Modified Fibrinogen Activates Macrophages and Promotes Coronary Endothelial Cell Inflammation","abstract":"Individuals with rheumatoid arthritis (RA) face increased cardiovascular mortality due to heart failure (HF) complications. Post-translational modifications, such as citrullination (CIT) and malondialdehyde-acetaldehyde (MAA) adduction, are implicated in RA pathogenesis. However, their role in RA-associated HF is not well understood. This study examines the deposition of MAA and CIT in cardiac tissues of RA-HF patients and investigates how MAA and CIT adducts on fibrinogen (FIB-MAA-CIT) drive crosstalk between macrophages and endothelial cells in vitro. We demonstrated elevated MAA and CIT adducts, strong perivascular MAA-CIT co-localization, and increased perivascular collagen deposition in the myocardium of RA-HF patients compared to non-RA HF controls. Treating human coronary artery endothelial cells (HCAECs) with FIB-MAA-CIT induced upregulation of inflammatory markers including MCP-1, IL-6, ICAM-1, and VCAM-1 compared to unmodified FIB. This response was amplified when HCAECs were treated with cell culture media obtained from FIB-MAA-CIT-stimulated macrophages. FIB-MAA-CIT activation of macrophages engaged NF-κB and p38 signaling pathways and inhibition of these pathways reduced FIB-MAA-CIT-mediated macrophage cytokine secretion and subsequent HCAEC responses. In summary, our findings support a novel mechanism by which endogenously modified proteins drive macrophage-endothelial cell crosstalk, promoting myocardial inflammation. Targeting these post-translational modifications may present novel therapeutic strategies to mitigate HF in RA.","journal":"Current Issues in Molecular Biology","year":2025,"id":581167,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9579,"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":1083839,"name":"Hannah J. Larsen","orcid":"0009-0004-2958-6444","position":1,"is_corresponding":false},{"id":366000,"name":"Michael J. Duryee","orcid":"0000-0001-9104-2238","position":2,"is_corresponding":false},{"id":903684,"name":"Nozima Aripova","orcid":"0000-0002-0920-8807","position":3,"is_corresponding":false},{"id":1492829,"name":"Engle E. Sharp","orcid":null,"position":4,"is_corresponding":false},{"id":367736,"name":"Carlos D. Hunter","orcid":null,"position":5,"is_corresponding":false},{"id":1492830,"name":"Kimberley Sinanan","orcid":null,"position":6,"is_corresponding":false},{"id":1492831,"name":"Henry C. Drvol","orcid":null,"position":7,"is_corresponding":false},{"id":1492832,"name":"M. Feely","orcid":null,"position":8,"is_corresponding":false},{"id":443093,"name":"Tate Johnson","orcid":"0000-0003-0335-4157","position":9,"is_corresponding":false},{"id":393308,"name":"Mabruka Alfaidi","orcid":"0000-0001-7970-0840","position":10,"is_corresponding":false},{"id":428993,"name":"Daniel R. Anderson","orcid":"0000-0001-6041-0077","position":11,"is_corresponding":false},{"id":1492833,"name":"Vineeth K. Reddy","orcid":null,"position":12,"is_corresponding":false},{"id":388572,"name":"Keshore R. Bidasee","orcid":"0000-0003-4165-8362","position":13,"is_corresponding":false},{"id":827124,"name":"Robert G. Bennett","orcid":"0000-0002-0755-6103","position":14,"is_corresponding":false},{"id":457086,"name":"Jill A. Poole","orcid":"0000-0002-6236-2563","position":15,"is_corresponding":false},{"id":342502,"name":"Geoffrey M. Thiele","orcid":"0000-0001-5688-8596","position":16,"is_corresponding":false},{"id":314417,"name":"Ted R. Mikuls","orcid":"0000-0002-0897-2272","position":17,"is_corresponding":false},{"id":1042847,"name":"Wenxian Zhou","orcid":"0000-0002-0558-9286","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-19T02:58:47.357782Z","pmid":"41296447","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":[]}