{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T08:51:06Z","timestamp":1765875066139,"version":"3.48.0"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T00:00:00Z","timestamp":1765843200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Excessive salt intake is a well-established risk factor for hypertension. However, the molecular mechanisms by which salt-induced endothelial dysfunction contributes to blood pressure elevation remain incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p>\n                      In this study, mice were fed a normal-salt diet (NSD) or high-salt diet (HSD) for 4 weeks, and primary bovine aortic endothelial cells (BAECs) were treated with varying concentrations of NaCl. HSD mice showed increased diastolic blood pressure and impaired acetylcholine-induced vasodilation, while sodium nitroprusside responses remained intact.\n                      <jats:italic>In vitro<\/jats:italic>\n                      experiments further confirmed salt-induced vascular endothelial dysfunction, high NaCl treatment reduced the proliferation, migration, and tube formation abilities of BAECs. Western blot analysis revealed that high salt exposure significantly increased O-GlcNAc modification of eNOS and upregulated O-GlcNAc transferase (OGT) expression, without altering total eNOS protein levels. Notably, nitric oxide (NO) bioavailability was significantly reduced both\n                      <jats:italic>in vivo<\/jats:italic>\n                      and\n                      <jats:italic>in vitro<\/jats:italic>\n                      . Treatment with the OGT inhibitor OSMI-1 reversed these changes and restored endothelium-dependent relaxation in HSD mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings suggest that high salt intake impairs endothelial function by enhancing O-GlcNAc of eNOS, thereby contributing to elevated diastolic blood pressure. The ability of OGT inhibition to reverse endothelial dysfunction highlights the therapeutic potential of targeting eNOS O-GlcNAc could be a promising approach for preventing salt-induced vascular damage and subsequent diastolic blood pressure elevation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2025.1730447","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T08:47:37Z","timestamp":1765874857000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["O-GlcNAcylation of eNOS in high-salt-induced thoracic aorta endothelial dysfunction in mice"],"prefix":"10.3389","volume":"16","author":[{"given":"Chang","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liuming","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Ling","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhan","family":"Lv","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1093\/ajh\/hpaf071","article-title":"Salt-induced vascular damage in hypertension involves redox activation of PARP\/TRPM2 signalling and inflammasome assembly","volume":"38","author":"Alves-Lopes","year":"2025","journal-title":"Am. J. Hypertens"},{"key":"B2","doi-asserted-by":"publisher","first-page":"101625","DOI":"10.1016\/j.redox.2020.101625","article-title":"Specific O-GlcNAc modification at Ser-615 modulates eNOS function","volume":"36","author":"Aulak","year":"2020","journal-title":"Redox Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1161\/01.hyp.31.1.499","article-title":"ET(A) receptor blockade prevents increased tissue endothelin-1, vascular hypertrophy, and endothelial dysfunction in salt-sensitive hypertension","volume":"31","author":"Barton","year":"1998","journal-title":"Hypertension"},{"key":"B4","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.vph.2011.11.003","article-title":"Activation of hexosamine pathway impairs nitric oxide (NO)-dependent arteriolar dilations by increased protein O-GlcNAcylation","volume":"56","author":"Beleznai","year":"2012","journal-title":"Vasc. Pharmacol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"111577","DOI":"10.1016\/j.cbi.2025.111577","article-title":"Platycodin D reverses tumor necrosis factor-alpha-induced endothelial dysfunction by increasing nitric oxide through G protein-coupled estrogen receptor-mediated eNOS activity","volume":"418","author":"Chae","year":"2025","journal-title":"Chem. Biol. Interact."},{"key":"B6","doi-asserted-by":"publisher","first-page":"2532","DOI":"10.1161\/STROKEAHA.108.545095","article-title":"eNOS mediates TO90317 treatment-induced angiogenesis and functional outcome after stroke in mice","volume":"40","author":"Chen","year":"2009","journal-title":"Stroke"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1958","DOI":"10.1016\/S0140-6736(19)30041-8","article-title":"Health effects of dietary risks in 195 countries, 1990-2017: a systematic analysis for the global burden of disease study 2017","volume":"393","author":"Collaborators","year":"2019","journal-title":"Lancet"},{"key":"B8","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1097\/HJH.0b013e32835c6ca8","article-title":"High dietary sodium intake impairs endothelium-dependent dilation in healthy salt-resistant humans","volume":"31","author":"Dupont","year":"2013","journal-title":"J. Hypertens."},{"key":"B9","doi-asserted-by":"publisher","first-page":"2550","DOI":"10.1001\/jama.2016.16106","article-title":"Reducing sodium intake in the population-reply","volume":"316","author":"Frieden","year":"2016","journal-title":"JAMA"},{"key":"B10","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1016\/j.pcad.2009.12.006","article-title":"Reducing population salt intake worldwide: from evidence to implementation","volume":"52","author":"He","year":"2010","journal-title":"Prog. Cardiovasc Dis."},{"key":"B11","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1016\/j.jacc.2019.11.055","article-title":"Salt reduction to prevent hypertension and cardiovascular disease: JACC state-of-the-art review","volume":"75","author":"He","year":"","journal-title":"J. Am. Coll. Cardiol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"19364","DOI":"10.1038\/s41598-020-76340-7","article-title":"Regulation of O-GlcNAcylation on endothelial nitric oxide synthase by glucose deprivation and identification of its O-GlcNAcylation sites","volume":"10","author":"He","year":"","journal-title":"Sci. Rep."},{"key":"B13","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1046\/j.1440-1681.2001.03435.x","article-title":"beta-Adrenoceptor blocking activities of nipradilol and its optical isomers in pig coronary artery","volume":"28","author":"Itomine","year":"2001","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"217957","DOI":"10.1016\/j.canlet.2025.217957","article-title":"O-GlcNAcylation of YBX1 drives a glycolysis-histone lactylation feedback loop in hepatocellular carcinoma","volume":"631","author":"Ji","year":"2025","journal-title":"Cancer Lett."},{"key":"B15","doi-asserted-by":"publisher","first-page":"156919","DOI":"10.1016\/j.phymed.2025.156919","article-title":"Unveiling XinJia-LuHuang granules' protective mechanism against atherosclerosis: integrating network pharmacology, metabolomics, and experimental validation","volume":"143","author":"Liu","year":"2025","journal-title":"Phytomedicine"},{"key":"B16","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.ab.2017.08.017","article-title":"Measurement of O-GlcNAcylated endothelial nitric oxide synthase by using 2',5'-ADP-Sepharose pull-down assay","volume":"537","author":"Long","year":"2017","journal-title":"Anal. Biochem."},{"key":"B17","doi-asserted-by":"publisher","first-page":"R1550","DOI":"10.1152\/ajpregu.00703.2006","article-title":"High salt intake reduces endothelium-dependent dilation of mouse arterioles via superoxide anion generated from nitric oxide synthase","volume":"292","author":"Nurkiewicz","year":"2007","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"e003733","DOI":"10.1136\/bmjopen-2013-003733","article-title":"Global, regional and national sodium intakes in 1990 and 2010: a systematic analysis of 24 h urinary sodium excretion and dietary surveys worldwide","volume":"3","author":"Powles","year":"2013","journal-title":"BMJ Open"},{"key":"B19","doi-asserted-by":"publisher","first-page":"H1341","DOI":"10.1152\/ajpheart.00202.2011","article-title":"Acute and chronic angiotensin-(1-7) restores vasodilation and reduces oxidative stress in mesenteric arteries of salt-fed rats","volume":"301","author":"Raffai","year":"2011","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"118885","DOI":"10.1016\/j.lfs.2020.118885","article-title":"Pregnancy decreases O-GlcNAc-modified proteins in systemic arteries of normotensive and spontaneously hypertensive rats","volume":"266","author":"Troiano","year":"2021","journal-title":"Life Sci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"5369","DOI":"10.1007\/s11010-025-05321-z","article-title":"Canagliflozin improves high-salt-induced aortic arteriosclerosis and premature aging in dahl salt-sensitive rats through the SIRT6\/HIF-1 alpha signaling pathway","volume":"480","author":"Wang","year":"2025","journal-title":"Mol. Cell Biochem."},{"key":"B22","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1038\/s41401-023-01181-9","article-title":"Role of thrombospondin-1 in high-salt-induced mesenteric artery endothelial impairment in rats","volume":"45","author":"Xu","year":"2024","journal-title":"Acta Pharmacol. Sin."},{"key":"B23","doi-asserted-by":"publisher","first-page":"4959","DOI":"10.1111\/bph.13265","article-title":"Angiotensin II stimulation alters vasomotor response to adenosine in mouse mesenteric artery: role for A1 and A2B adenosine receptors","volume":"172","author":"Yadav","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"2415","DOI":"10.1161\/HYPERTENSIONAHA.124.23115","article-title":"Transient high salt intake promotes T-Cell-Mediated hypertensive vascular injury","volume":"81","author":"Yakoub","year":"2024","journal-title":"Hypertension"},{"key":"B25","doi-asserted-by":"publisher","first-page":"30133","DOI":"10.1074\/jbc.M403773200","article-title":"Dynamic O-GlcNAc modification of nucleocytoplasmic proteins in response to stress. A survival response of Mammalian cells","volume":"279","author":"Zachara","year":"2004","journal-title":"J. Biol. Chem."},{"key":"B26","doi-asserted-by":"publisher","first-page":"177807","DOI":"10.1016\/j.ejphar.2025.177807","article-title":"Morin ameliorates coronary artery relaxation by activating TRPV4-eNOS-NO signalling in high-salt diet-fed rats","volume":"1002","author":"Zhang","year":"2025","journal-title":"Eur. J. Pharmacol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1111\/cts.12770","article-title":"Potential protective effects of the water-soluble Chinese propolis on hypertension induced by high-salt intake","volume":"13","author":"Zhou","year":"2020","journal-title":"Clin. Transl. Sci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"e14530","DOI":"10.1002\/advs.202414530","article-title":"Hypoglycemia induces diabetic macrovascular endothelial dysfunction via endothelial cell PANoptosis, macrophage polarization, and VSMC fibrosis","volume":"12","author":"Zuo","year":"2025","journal-title":"Adv. Sci. (Weinh)"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1730447\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T08:47:41Z","timestamp":1765874861000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1730447\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,16]]},"references-count":28,"alternative-id":["10.3389\/fphar.2025.1730447"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1730447","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,16]]},"article-number":"1730447"}}