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In this study, transgenic Sickle Cell Anemia mice (SS mice) treated with CDDO-Methyl (CDDO-Me), a potent Nrf2 activator, showed reduced progression of hemolytic anemia with aging, but surprisingly also showed reduced endothelial function. Pulmonary vessels isolated from SS mice treated for 4\u00a0months with CDDO-Me displayed a diminished response to nitric oxide (NO)-induced vasodilation compared to littermates given vehicle. It is unclear what molecular mechanism underly the vascular impairment, however, our <jats:italic>in vitro<\/jats:italic> assays revealed that CDDO-Me induced the expression of the endothelin receptor (ET<jats:sub>A<\/jats:sub> and ET<jats:sub>B<\/jats:sub>) in vascular smooth muscle cells. Endothelin signaling is associated with increased vascular tone and vasoconstriction. This study underscores the importance of pre-clinical benefit-risk investigations of Nrf2 activating compounds which may be used to treat patients with SCD.<\/jats:p>","DOI":"10.3389\/fphar.2022.880834","type":"journal-article","created":{"date-parts":[[2022,5,10]],"date-time":"2022-05-10T07:18:41Z","timestamp":1652167121000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Nrf2 Activation With CDDO-Methyl Promotes Beneficial and Deleterious Clinical Effects in Transgenic Mice With Sickle Cell Anemia"],"prefix":"10.3389","volume":"13","author":[{"given":"Chibueze A.","family":"Ihunnah","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samit","family":"Ghosh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott","family":"Hahn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam C.","family":"Straub","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Solomon F.","family":"Ofori-Acquah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1177\/1756285614564152","article-title":"Dimethyl Fumarate in the Treatment of Relapsing-Remitting Multiple Sclerosis: an Overview","volume":"8","author":"Bomprezzi","year":"2015","journal-title":"Ther. 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