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Oxidized LDL (ox\u2010LDL) is a key pathological factor in endothelial dysfunction. In the present study we examined the role of ENaC in ox\u2010LDL\u2010induced endothelial dysfunction and its associated signal transduction pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Patch clamp techniques combined with pharmacological approaches were used to examine ENaC activity in the endothelial cells of a split\u2010open mouse thoracic aorta. Western blot analysis was used to determine ENaC expression in the aorta. The aorta relaxation was measured using a wire myograph assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Ox\u2010LDL, but not LDL, significantly increased ENaC activity in the endothelial cells attached to split\u2010open thoracic aortas, and the increase was inhibited by a lectin\u2010like ox\u2010LDL receptor\u20101 (LOX\u20101) antagonist (\u03ba\u2010carrageenan), an NADPH oxidase inhibitor (apocynin), and a scavenger of ROS (TEMPOL). Sodium nitroprusside, an NO donor, diminished the ox\u2010LDL\u2010mediated activation of ENaC, and this effect was abolished by inhibiting soluble guanylate cyclase (sGC) and PKG. Ox\u2010LDL reduced the endothelium\u2010dependent vasodilatation of the aorta pectoralis induced by ACh, and this reduction was partially restored by blocking ENaC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Ox\u2010LDL stimulates ENaC in endothelial cells through LOX\u20101 receptor\u2010mediated activation of NADPH oxidase and accumulation of intracellular ROS. Since the stimulation of ENaC can be reversed by elevating NO, we suggest that both inhibition of ENaC and an elevation of NO may protect the endothelium from ox\u2010LDL\u2010induced dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Linked Articles<\/jats:title><jats:p>This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v175.8\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v175.8\/issuetoc<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13853","type":"journal-article","created":{"date-parts":[[2017,5,8]],"date-time":"2017-05-08T05:45:38Z","timestamp":1494222338000},"page":"1318-1328","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Oxidized low\u2010density lipoprotein stimulates epithelial sodium channels in endothelial cells of mouse thoracic aorta"],"prefix":"10.1111","volume":"175","author":[{"given":"Chen","family":"Liang","sequence":"first","affiliation":[{"name":"Departments of Cardiology and Clinical Pharmacy Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment  Harbin P. 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