{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T18:34:24Z","timestamp":1782930864452,"version":"3.54.5"},"reference-count":29,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T00:00:00Z","timestamp":1684195200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Polish National Science Centre","doi-asserted-by":"publisher","award":["UMO-2018\/29\/B\/NZ5\/02629"],"award-info":[{"award-number":["UMO-2018\/29\/B\/NZ5\/02629"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004281","name":"Polish National Science Centre","doi-asserted-by":"publisher","award":["N41\/DBS\/000003"],"award-info":[{"award-number":["N41\/DBS\/000003"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009045","name":"Dean of the Faculty of Medicine, Jagiellonian University Medical College","doi-asserted-by":"publisher","award":["UMO-2018\/29\/B\/NZ5\/02629"],"award-info":[{"award-number":["UMO-2018\/29\/B\/NZ5\/02629"]}],"id":[{"id":"10.13039\/100009045","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009045","name":"Dean of the Faculty of Medicine, Jagiellonian University Medical College","doi-asserted-by":"publisher","award":["N41\/DBS\/000003"],"award-info":[{"award-number":["N41\/DBS\/000003"]}],"id":[{"id":"10.13039\/100009045","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Aortic stenosis (AS) is associated with hypofibrinolysis, but its mechanism is poorly understood. We investigated whether LDL cholesterol affects plasminogen activator inhibitor 1 (PAI-1) expression, which may contribute to hypofibrinolysis in AS. Stenotic valves were obtained from 75 severe AS patients during valve replacement to assess lipids accumulation, together with PAI-1 and nuclear factor-\u03baB (NF-\u03baB) expression. Five control valves from autopsy healthy individuals served as controls. The expression of PAI-1 in valve interstitial cells (VICs) after LDL stimulation was assessed at protein and mRNA levels. PAI-1 activity inhibitor (TM5275) and NF-\u03baB inhibitor (BAY 11-7082) were used to suppress PAI-1 activity or NF-\u03baB pathway. Clot lysis time (CLT) was performed to assess fibrinolytic capacity in VICs cultures. Solely AS valves showed PAI-1 expression, the amount of which was correlated with lipid accumulation and AS severity and co-expressed with NF-\u03baB. In vitro VICs showed abundant PAI-1 expression. LDL stimulation increased PAI-1 levels in VICs supernatants and prolonged CLT. PAI-1 activity inhibition shortened CLT, while NF-\u03baB inhibition decreased PAI-1 and SERPINE1 expression in VICs, its level in supernatants and shortened CLT. In severe AS, valvular PAI-1 overexpression driven by lipids accumulation contributes to hypofibrinolysis and AS severity.<\/jats:p>","DOI":"10.3390\/cells12101402","type":"journal-article","created":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T01:52:41Z","timestamp":1684288361000},"page":"1402","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["PAI-1 Overexpression in Valvular Interstitial Cells Contributes to Hypofibrinolysis in Aortic Stenosis"],"prefix":"10.3390","volume":"12","author":[{"given":"Magdalena","family":"Kopytek","sequence":"first","affiliation":[{"name":"Thromboembolic Disorders Department, Institute of Cardiology, Jagiellonian University Medical College, 80 Pradnicka St., 31-202 Krakow, Poland"},{"name":"Krakow Centre for Medical Research and Technologies, John Paul II Hospital, 80 Pradnicka St., 31-202 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1762-308X","authenticated-orcid":false,"given":"Micha\u0142","family":"Z\u0105bczyk","sequence":"additional","affiliation":[{"name":"Thromboembolic Disorders Department, Institute of Cardiology, Jagiellonian University Medical College, 80 Pradnicka St., 31-202 Krakow, Poland"},{"name":"Krakow Centre for Medical Research and Technologies, John Paul II Hospital, 80 Pradnicka St., 31-202 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4077-1232","authenticated-orcid":false,"given":"Piotr","family":"Mazur","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA"},{"name":"Department of Cardiovascular Surgery and Transplantology, Institute of Cardiology, Jagiellonian University Medical College, 80 Pradnicka St., 31-202 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anetta","family":"Undas","sequence":"additional","affiliation":[{"name":"Thromboembolic Disorders Department, Institute of Cardiology, Jagiellonian University Medical College, 80 Pradnicka St., 31-202 Krakow, Poland"},{"name":"Krakow Centre for Medical Research and Technologies, John Paul II Hospital, 80 Pradnicka St., 31-202 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Natorska","sequence":"additional","affiliation":[{"name":"Thromboembolic Disorders Department, Institute of Cardiology, Jagiellonian University Medical College, 80 Pradnicka St., 31-202 Krakow, Poland"},{"name":"Krakow Centre for Medical Research and Technologies, John Paul II Hospital, 80 Pradnicka St., 31-202 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1016\/0735-1097(93)90249-Z","article-title":"Prevalence of aortic valve abnormalities in the elderly: An echocardiographic study of a random population sample","volume":"21","author":"Lindroos","year":"1993","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.jacc.2015.05.066","article-title":"Calcification in Aortic Stenosis: The Skeleton Key","volume":"66","author":"Pawade","year":"2015","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1160\/TH14-10-0861","article-title":"Blood coagulation and fibrinolysis in aortic valve stenosis: Links with inflammation and calcification","volume":"114","author":"Natorska","year":"2015","journal-title":"Thromb. Haemost."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.2353\/ajpath.2007.070251","article-title":"The emerging role of valve interstitial cell phenotypes in regulating heart valve pathobiology","volume":"171","author":"Liu","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Stubblefield, W.B., Alves, N.J., Rondina, M.T., and Kline, J.A. (2016). Variable Resistance to Plasminogen Activator Initiated Fibrinolysis for Intermediate-Risk Pulmonary Embolism. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0148747"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1111\/jth.12122","article-title":"Impaired fibrinolysis is associated with the severity of aortic stenosis in humans","volume":"11","author":"Natorska","year":"2013","journal-title":"J. Thromb. Haemost."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Siudut, J., Natorska, J., Wypasek, E., Wiewi\u00f3rka, \u0141., Ostrowska-Kaim, E., Wi\u015bniowska-\u015amia\u0142ek, S., Plens, K., Legutko, J., and Undas, A. (2020). Impaired Fibrinolysis in Patients with Isolated Aortic Stenosis is Associated with Enhanced Oxidative Stress. J. Clin. Med., 9.","DOI":"10.3390\/jcm9062002"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1002\/path.2681","article-title":"Plasmin induces apoptosis of aortic valvular myofibroblasts","volume":"221","author":"Kochtebane","year":"2010","journal-title":"J. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s12959-018-0166-4","article-title":"Association between plasminogen activator inhibitor-1 and cardiovascular events: A systematic review and meta-analysis","volume":"16","author":"Jung","year":"2018","journal-title":"Thromb. J."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Rahman, F.A., and Krause, M.P. (2020). PAI-1, the Plasminogen System, and Skeletal Muscle. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197066"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e72","DOI":"10.1111\/j.1755-5922.2010.00171.x","article-title":"Plasminogen activator inhibitor-1 (PAI-1): A key factor linking fibrinolysis and age-related subclinical and clinical conditions","volume":"28","author":"Cesari","year":"2010","journal-title":"Cardiovasc. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.carpath.2005.01.002","article-title":"Inflammatory regulation of extracellular matrix remodeling in calcific aortic valve stenosis","volume":"14","author":"Kaden","year":"2005","journal-title":"Cardiovasc. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2562","DOI":"10.1007\/s00125-021-05545-w","article-title":"Diabetes concomitant to aortic stenosis is associated with increased expression of NF-\u03baB and more pronounced valve calcification","volume":"64","author":"Kopytek","year":"2021","journal-title":"Diabetologia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.atherosclerosis.2022.01.011","article-title":"Apolipoproteins and lipoprotein(a) as factors modulating fibrin clot properties in patients with severe aortic stenosis","volume":"344","author":"Siudut","year":"2022","journal-title":"Atherosclerosis"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1093\/eurheartj\/ehab395","article-title":"ESC\/EACTS Scientific Document Group. 2021 ESC\/EACTS Guidelines for the management of valvular heart disease","volume":"43","author":"Vahanian","year":"2022","journal-title":"Eur. Heart J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1186\/s12933-020-01068-7","article-title":"Accumulation of advanced glycation end products (AGEs) is associated with the severity of aortic stenosis in patients with concomitant type 2 diabetes","volume":"19","author":"Kopytek","year":"2020","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"C29","DOI":"10.1152\/ajpcell.00137.2007","article-title":"Expression of functional Toll-like receptors 2 and 4 in human aortic valve interstitial cells: Potential roles in aortic valve inflammation and stenosis","volume":"294","author":"Meng","year":"2008","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"106679","DOI":"10.1016\/j.vph.2020.106679","article-title":"Effects of rivaroxaban and dabigatran on local expression of coagulation and inflammatory factors within human aortic stenotic valves","volume":"130","author":"Wypasek","year":"2020","journal-title":"Vascul. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4704","DOI":"10.1167\/iovs.15-18663","article-title":"Oxidized Lipoprotein Uptake Through the CD36 Receptor Activates the NLRP3 Inflammasome in Human Retinal Pigment Epithelial Cells","volume":"57","author":"Gnanaguru","year":"2016","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.thromres.2013.04.003","article-title":"TM5275 prolongs secreted tissue plasminogen activator retention and enhances fibrinolysis on vascular endothelial cells","volume":"132","author":"Yasui","year":"2013","journal-title":"Thromb. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1161\/ATVBAHA.120.314143","article-title":"A Role for MMP-10 (Matrix Metalloproteinase-10) in Calcific Aortic Valve Stenosis","volume":"40","author":"Matilla","year":"2020","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1111\/jth.14002","article-title":"Subcommittee on Factor XIII and Fibrinogen, and the Subcommittee on Fibrinolysis. An international study on the feasibility of a standardized combined plasma clot turbidity and lysis assay: Communication from the SSC of the ISTH","volume":"16","author":"Pieters","year":"2018","journal-title":"J. Thromb. Haemost."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1160\/TH10-09-0612","article-title":"Fibrin presence within aortic valves in patients with aortic stenosis: Association with in vivo thrombin generation and fibrin clot properties","volume":"105","author":"Natorska","year":"2011","journal-title":"Thromb. Haemost."},{"key":"ref_24","first-page":"2094","article-title":"Expression of plasminogen activator inhibitors 1 and 2 in lung cancer and their role in tumor progression","volume":"5","author":"Robert","year":"1999","journal-title":"Clin. Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2427","DOI":"10.1002\/jcb.25223","article-title":"Tumor Necrosis Factor Related Apoptosis Inducing Ligand (Trail) in endothelial response to biomechanical and biochemical stresses in arteries","volume":"116","author":"Centurione","year":"2015","journal-title":"J. Cell. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2389","DOI":"10.1046\/j.1538-7836.2003.00437.x","article-title":"Tissue- and agonist-specific regulation of human and murine plasminogen activator inhibitor-1 promoters in transgenic mice","volume":"1","author":"Eren","year":"2003","journal-title":"J. Thromb. Haemost."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.atherosclerosis.2013.12.023","article-title":"Visceral adipose tissue as a source of inflammation and promoter of atherosclerosis","volume":"233","author":"Alexopoulos","year":"2014","journal-title":"Atherosclerosis"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1161\/ATVBAHA.119.313775","article-title":"Drug Targeting of Plasminogen Activator Inhibitor-1 Inhibits Metabolic Dysfunction and Atherosclerosis in a Murine Model of Metabolic Syndrome","volume":"40","author":"Khoukaz","year":"2020","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ramadass, V., Vaiyapuri, T., and Tergaonkar, V. (2020). Small Molecule NF-\u03baB Pathway Inhibitors in Clinic. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21145164"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/10\/1402\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:36:17Z","timestamp":1760124977000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/10\/1402"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,16]]},"references-count":29,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["cells12101402"],"URL":"https:\/\/doi.org\/10.3390\/cells12101402","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,16]]}}}