{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T05:38:10Z","timestamp":1769578690761,"version":"3.49.0"},"reference-count":39,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2023,11,28]],"date-time":"2023-11-28T00:00:00Z","timestamp":1701129600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fund for Scientific Research","award":["1S33720N and 11C6321N"],"award-info":[{"award-number":["1S33720N and 11C6321N"]}]},{"name":"Fund for Scientific Research","award":["1S33720N and 11C6321N"],"award-info":[{"award-number":["1S33720N and 11C6321N"]}]},{"name":"FWO Flanders","award":["1804320N"],"award-info":[{"award-number":["1804320N"]}]},{"DOI":"10.13039\/501100013845","name":"Foundation against Cancer","doi-asserted-by":"crossref","award":["2021-034"],"award-info":[{"award-number":["2021-034"]}],"id":[{"id":"10.13039\/501100013845","id-type":"DOI","asserted-by":"crossref"}]},{"name":"DOCPRO4 grant of the Research Council of the University of Antwerp","award":["39984"],"award-info":[{"award-number":["39984"]}]},{"name":"European Union's Horizon 2020 Research and Innovation Program","award":["No858070"],"award-info":[{"award-number":["No858070"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Apart from cardiotoxicity, the chemotherapeutic agent doxorubicin (DOX) provokes acute and long-term vascular toxicity. Dexrazoxane (DEXRA) is an effective drug for treatment of DOX-induced cardiotoxicity, yet it remains currently unknown whether DEXRA prevents vascular toxicity associated with DOX. Accordingly, the present study aimed to evaluate the protective potential of DEXRA against DOX-related vascular toxicity in a previously-established <jats:italic>in vivo<\/jats:italic> and <jats:italic>ex vivo<\/jats:italic> model of vascular dysfunction induced by 16 hour (h) DOX exposure. Vascular function was evaluated in the thoracic aorta in organ baths, 16h after administration of DOX (4 mg\/kg) or DOX with DEXRA (40 mg\/kg) to male C57BL6\/J mice. In parallel, vascular reactivity was evaluated after <jats:italic>ex vivo<\/jats:italic> incubation (16h) of murine aortic segments with DOX (1 \u03bcM) or DOX with DEXRA (10 \u03bcM). In both <jats:italic>in vivo<\/jats:italic> and <jats:italic>ex vivo<\/jats:italic> experiments, DOX impaired acetylcholine-stimulated endothelium-dependent vasodilation. In the <jats:italic>ex vivo<\/jats:italic> setting, DOX additionally attenuated phenylephrine-elicited vascular smooth muscle cell (VSMC) contraction. Importantly, DEXRA failed to prevent DOX-induced endothelial dysfunction and hypocontraction. Furthermore, RT-qPCR and Western blotting showed that DOX decreased the protein levels of topoisomerase-II\u03b2 (TOP-II\u03b2), a key target of DEXRA, in the heart, but not in the aorta. Additionally, the effect of N-acetylcysteine (NAC, 10 \u03bcM), a reactive oxygen species (ROS) scavenger, was evaluated <jats:italic>ex vivo<\/jats:italic>. NAC did not prevent DOX-induced impairment of acetylcholine-stimulated vasodilation. In conclusion, our results show that DEXRA fails to prevent vascular toxicity resulting from 16h DOX treatment. This may relate to DOX provoking vascular toxicity in a ROS- and TOP-II\u03b2-independent way, at least in the evaluated acute setting. However, it is important to mention that these findings only apply to the acute (16h) treatment period, and further research is warranted to delineate the therapeutic potential of DEXRA against vascular toxicity associated with longer-term repetitive DOX dosing.<\/jats:p>","DOI":"10.1371\/journal.pone.0294848","type":"journal-article","created":{"date-parts":[[2023,11,28]],"date-time":"2023-11-28T19:07:42Z","timestamp":1701198462000},"page":"e0294848","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Dexrazoxane does not mitigate early vascular toxicity induced by doxorubicin in mice"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9102-5366","authenticated-orcid":true,"given":"Matthias","family":"Bosman","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dustin N.","family":"Kr\u00fcger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kasper","family":"Favere","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3848-8702","authenticated-orcid":true,"given":"Guido R. 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