{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T07:14:46Z","timestamp":1773299686644,"version":"3.50.1"},"reference-count":40,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2013,3,25]],"date-time":"2013-03-25T00:00:00Z","timestamp":1364169600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2013,4]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">L<\/jats:styled-content>\u2010gulonolactone oxidase\u2010deficient (<jats:styled-content style=\"fixed-case\">G<\/jats:styled-content>ulo<jats:sup>(\u2010\/\u2010)<\/jats:sup>) mice were used to study the effects of ascorbate deficiency on aortic relaxation by nitroglycerin (<jats:styled-content style=\"fixed-case\">GTN<\/jats:styled-content>) with focus on changes in the expression and activity of vascular aldehyde dehydrogenase\u20102 (<jats:styled-content style=\"fixed-case\">ALDH2<\/jats:styled-content>), which catalyses<jats:styled-content style=\"fixed-case\">GTN<\/jats:styled-content>bioactivation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Ascorbate deficiency was induced in<jats:styled-content style=\"fixed-case\">G<\/jats:styled-content>ulo<jats:sup>(\u2010\/\u2010)<\/jats:sup>mice by ascorbate deprivation for 4 weeks. Some of the animals were concomitantly treated with the proteasome inhibitor bortezomib and effects compared with ascorbate\u2010supplemented<jats:styled-content style=\"fixed-case\">G<\/jats:styled-content>ulo<jats:sup>(\u2010\/\u2010)<\/jats:sup>, untreated or nitrate\u2010tolerant wild\u2010type mice. Aortic relaxation of the experimental groups to<jats:styled-content style=\"fixed-case\">GTN<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\">ACh<\/jats:styled-content>and a<jats:styled-content style=\"fixed-case\">NO<\/jats:styled-content>donor was studied. Changes in<jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content>and protein expression of vascular<jats:styled-content style=\"fixed-case\">ALDH2<\/jats:styled-content>were quantified by<jats:styled-content style=\"fixed-case\">qPCR<\/jats:styled-content>and immunoblotting, respectively, and aortic<jats:styled-content style=\"fixed-case\">GTN<\/jats:styled-content>denitration rates determined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Like<jats:styled-content style=\"fixed-case\">GTN<\/jats:styled-content>treatment, ascorbate deprivation induced vascular tolerance to<jats:styled-content style=\"fixed-case\">GTN<\/jats:styled-content>that was associated with markedly decreased rates of<jats:styled-content style=\"fixed-case\">GTN<\/jats:styled-content>denitration. Ascorbate deficiency did not affect<jats:styled-content style=\"fixed-case\">ALDH2 mRNA<\/jats:styled-content>levels, but reduced<jats:styled-content style=\"fixed-case\">ALDH2<\/jats:styled-content>protein expression and the total amount of ubiquitinated proteins to about 40% of wild\u2010type controls. These effects were largely prevented by ascorbate supplementation or treating<jats:styled-content style=\"fixed-case\">G<\/jats:styled-content>ulo<jats:sup>(\u2010\/\u2010)<\/jats:sup>mice with the 26S proteasome inhibitor bortezomib.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Our data indicate that ascorbate deficiency results in vascular tolerance to<jats:styled-content style=\"fixed-case\">GTN<\/jats:styled-content>via proteasomal degradation of<jats:styled-content style=\"fixed-case\">ALDH2<\/jats:styled-content>. The results support the view that impaired<jats:styled-content style=\"fixed-case\">ALDH2<\/jats:styled-content>\u2010catalysed metabolism of<jats:styled-content style=\"fixed-case\">GTN<\/jats:styled-content>contributes significantly to the development of vascular nitrate tolerance and reveal a hitherto unrecognized protective effect of ascorbate in the vasculature.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12081","type":"journal-article","created":{"date-parts":[[2012,11,30]],"date-time":"2012-11-30T06:20:22Z","timestamp":1354256422000},"page":"1868-1877","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Tolerance to nitroglycerin through proteasomal down\u2010regulation of aldehyde dehydrogenase\u20102 in a genetic mouse model of ascorbate deficiency"],"prefix":"10.1111","volume":"168","author":[{"given":"G","family":"W\u00f6lkart","sequence":"first","affiliation":[{"name":"Department of Pharmacology and 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