{"doi":"10.1172/jci196714","title":"Plasminogen activator inhibitor 1 promotes aortic aging–like pathophysiology in humans and mice","abstract":"Plasminogen activator inhibitor 1 (PAI-1), encoded by SERPINE1, contributes to age-related cardiovascular disease (CVD) and other aging-related pathologies. Humans with a heterozygous loss-of-function SERPINE1 variant exhibit protection against aging and cardiometabolic dysfunction. We engineered a mouse model mimicking the human mutation (Serpine1TA700/+) and compared cardiovascular responses with WT littermates. Serpine1TA700/+ mice lived 17% longer than did littermate control mice. Under l-NG-nitro-arginine methyl ester-induced (l-NAME-induced) vascular stress, Serpine1TA700/+ mice exhibited diminished pulse wave velocity (PWV), lower systolic blood pressure (SBP), and preserved left ventricular diastolic function compared with controls. Conversely, PAI-1-overexpressing mice had measurements indicating accelerated cardiovascular aging. Single-cell transcriptomics of Serpine1TA700/+ aortas revealed a vascular-protective mechanism with downregulation of the extracellular matrix regulators Ccn1 and Itgb1. Serpine1TA700/+ aortas were also enriched in a cluster of smooth muscle cells that exhibited plasticity. Finally, PAI-1 pharmacological inhibition normalized SBP and reversed l-NAME-induced PWV elevation. These findings demonstrate that PAI-1 reduction protects against cardiovascular aging-related phenotypes, while PAI-1 excess promotes vascular pathological changes. Taken together, PAI-1 inhibition represents a promising strategy to mitigate age-related CVD.","journal":"Journal of Clinical Investigation","year":2025,"id":547289,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9637,"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":1440142,"name":"Anthony Kalousdian","orcid":null,"position":1,"is_corresponding":false},{"id":634577,"name":"Mesut Eren","orcid":"0000-0003-4482-9550","position":2,"is_corresponding":false},{"id":569801,"name":"Saul Soberanes","orcid":"0000-0002-6820-9711","position":3,"is_corresponding":false},{"id":1440143,"name":"Andrew Decker","orcid":null,"position":4,"is_corresponding":false},{"id":635571,"name":"Elizabeth Lux","orcid":null,"position":5,"is_corresponding":false},{"id":1440144,"name":"Benjamin W. Zywicki","orcid":null,"position":6,"is_corresponding":false},{"id":704432,"name":"Brian Dinh","orcid":null,"position":7,"is_corresponding":false},{"id":1440145,"name":"Bedirhan Boztepe","orcid":null,"position":8,"is_corresponding":false},{"id":906186,"name":"Baljash Cheema","orcid":"0000-0002-4105-0579","position":9,"is_corresponding":false},{"id":456355,"name":"Carla M. Cuda","orcid":"0000-0002-2022-8171","position":10,"is_corresponding":false},{"id":232815,"name":"Hiam Abdala‐Valencia","orcid":"0000-0003-3384-5299","position":11,"is_corresponding":false},{"id":1440146,"name":"Arun Sivakumar","orcid":null,"position":12,"is_corresponding":false},{"id":634581,"name":"Toshio Miyata","orcid":"0000-0001-9153-5024","position":13,"is_corresponding":false},{"id":573861,"name":"Lisa D. Wilsbacher","orcid":"0000-0002-3676-0680","position":14,"is_corresponding":false},{"id":634582,"name":"Douglas E. Vaughan","orcid":"0000-0002-8407-6613","position":15,"is_corresponding":false},{"id":1282953,"name":"Alireza Khoddam","orcid":null,"position":0,"is_corresponding":true}],"reference_count":71,"raw_metadata":null,"created_at":"2026-07-19T02:53:41.314800Z","pmid":"41026613","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":[]}