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PDC2021-121817-100"],"award-info":[{"award-number":["MICINN\/AEI\/FEDER\/EU PDC2021-121817-100"]}]},{"name":"UFV research grant 2019","award":["SBPLY\/19\/180501\/000055"],"award-info":[{"award-number":["SBPLY\/19\/180501\/000055"]}]},{"name":"UFV research grant 2019","award":["ISCIII PI20-00930"],"award-info":[{"award-number":["ISCIII PI20-00930"]}]},{"name":"UFV research grant 2019","award":["P2022\/BMD7223 CIFRA_COR_CM"],"award-info":[{"award-number":["P2022\/BMD7223 CIFRA_COR_CM"]}]},{"name":"UFV research grant 2019","award":["MINECO\/AEI\/FEDER\/EU SAF2017-87342-R"],"award-info":[{"award-number":["MINECO\/AEI\/FEDER\/EU SAF2017-87342-R"]}]},{"name":"UFV research grant 2019","award":["MICINN\/AEI\/FEDER\/EU PID2020-118371RB-I00"],"award-info":[{"award-number":["MICINN\/AEI\/FEDER\/EU PID2020-118371RB-I00"]}]},{"name":"UFV research grant 2019","award":["MICINN\/AEI\/FEDER\/EU PDC2021-121817-100"],"award-info":[{"award-number":["MICINN\/AEI\/FEDER\/EU PDC2021-121817-100"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Vascular aging is associated with the development of cardiovascular complications, in which endothelial cell senescence (ES) may play a critical role. Nitric oxide (NO) prevents human ES through inhibition of oxidative stress, and inflammatory signaling by mechanisms yet to be elucidated. Endothelial cells undergo an irreversible growth arrest and alter their functional state after a finite number of divisions, a phenomenon called replicative senescence. We assessed the contribution of NO during replicative senescence of human aortic (HAEC) and coronary (CAEC) endothelial cells, in which accumulation of the senescence marker SA-\u03b2-Gal was quantified by \u03b2-galactosidase staining on cultured cells. We found a negative correlation in passaged cell cultures from P0 to P12, between a reduction in NO production with increased ES and the formation of reactive oxygen (ROS) and nitrogen (ONOO\u2212) species, indicative of oxidative and nitrosative stress. The effect of ES was evidenced by reduced expression of endothelial Nitric Oxide Synthase (eNOS), Interleukin Linked Kinase (ILK), and Heat shock protein 90 (Hsp90), alongside a significant increase in the BH2\/BH4 ratio, inducing the uncoupling of eNOS, favoring the production of superoxide and peroxynitrite species, and fostering an inflammatory environment, as confirmed by the levels of Cyclophilin A (CypA) and its receptor Extracellular Matrix Metalloprotease Inducer (EMMPRIN). NO prevents ES by preventing the uncoupling of eNOS, in which oxidation of BH4, which plays a key role in eNOS producing NO, may play a critical role in launching the release of free radical species, triggering an aging-related inflammatory response.<\/jats:p>","DOI":"10.3390\/ijms25189890","type":"journal-article","created":{"date-parts":[[2024,9,13]],"date-time":"2024-09-13T05:31:44Z","timestamp":1726205504000},"page":"9890","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Replicative Endothelial Cell Senescence May Lead to Endothelial Dysfunction by Increasing the BH2\/BH4 Ratio Induced by Oxidative Stress, Reducing BH4 Availability, and Decreasing the Expression of eNOS"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4331-534X","authenticated-orcid":false,"given":"Ignacio","family":"Hernandez-Navarro","sequence":"first","affiliation":[{"name":"Unidad Mixta de 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Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6520-4416","authenticated-orcid":false,"given":"Javier","family":"Diez-Mata","sequence":"additional","affiliation":[{"name":"Unidad Mixta de Investigaci\u00f3n Cardiovascular Universidad Francisco de Vitoria, Hospital Universitario Ram\u00f3n y Cajal (IRYCIS), 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1536-4216","authenticated-orcid":false,"given":"Laura","family":"Tesoro","sequence":"additional","affiliation":[{"name":"Unidad Mixta de Investigaci\u00f3n Cardiovascular Universidad Francisco de Vitoria, Hospital Universitario Ram\u00f3n y Cajal (IRYCIS), 28034 Madrid, Spain"},{"name":"Facultad de Medicina, Universidad Francisco de Vitoria, 28223 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Jimenez-Guirado","sequence":"additional","affiliation":[{"name":"Unidad 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Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose Luis","family":"Zamorano","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"},{"name":"Departamento de Cardiolog\u00eda, Hospital Universitario Ram\u00f3n y Cajal (IRYCIS), 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3977-6581","authenticated-orcid":false,"given":"Marta","family":"Saura","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"},{"name":"Unidad de Fisiolog\u00eda, Departamento de Biolog\u00eda de Sistemas, Universidad de Alcal\u00e1 (IRYCIS), 28871 Alcala de Henares, 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