{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T07:03:58Z","timestamp":1792047838423,"version":"4.4.0"},"reference-count":75,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,6,17]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">Friedreich's ataxia (FA) is a genetic disorder caused by a severe decrease in FXN (frataxin) protein expression in mitochondria. The clinical manifestation of this disorder is a cerebellar ataxia; however, the common lethal component in FA is cardiomyopathy.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              A conditional Fxn\n              <jats:sup>flox\/null<\/jats:sup>\n              ::MCK\u2010Cre knockout (FXN\u2010cKO) mouse model was used to mimic the late\u2010stage severe cardiomyopathy in FA. Nrf2 (nuclear factor erythroid 2\u2010related factor 2) inducers, omaveloxolone and dimethyl fumarate (DMF), were independently tested in this mouse model to determine the effects on cardiac health and lifespan.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Omaveloxolone significantly improved cardiac contractile function and markers of heart failure in FA such as\n              <jats:italic toggle=\"no\">Nppb<\/jats:italic>\n              ,\n              <jats:italic toggle=\"no\">Aldh1a3<\/jats:italic>\n              , and\n              <jats:italic toggle=\"no\">Gdf15<\/jats:italic>\n              . Despite improvement in cardiac function, omaveloxolone did not prevent premature death in FXN\u2010cKO animals and notably accelerated death in FXN\u2010cKO females. Omaveloxolone decreased oxidative stress and inflammatory marker IL1\u03b2 (interleukin\u20101 beta), and stimulated\n              <jats:italic toggle=\"no\">Nqo1<\/jats:italic>\n              gene expression above control level. DMF restored elevated\n              <jats:italic toggle=\"no\">HO\u20101<\/jats:italic>\n              (\n              <jats:italic toggle=\"yes\">Hmox<\/jats:italic>\n              ) expression and significantly increased\n              <jats:italic toggle=\"no\">Sirt1<\/jats:italic>\n              expression. Although both omaveloxolone and DMF restored decreased SERCA2 (\n              <jats:italic toggle=\"yes\">Atp2a)<\/jats:italic>\n              and MCU (\n              <jats:italic toggle=\"yes\">Mcu<\/jats:italic>\n              ) expression and ameliorated elevated phosphorylation of CaMKII\u03b4 at Thr\n              <jats:sup>286<\/jats:sup>\n              site in FA hearts, DMF did not improve cardiac contractile function and survival. Furthermore, neither omaveloxolone or DMF decreased hypertrophy and fibrosis (Masson trichrome staining and\n              <jats:italic toggle=\"no\">Lgals3<\/jats:italic>\n              expression) or rescued impaired mitochondrial function and integrative stress response in FXN\u2010cKO hearts.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">These data demonstrate that omaveloxolone significantly improved contractile function but not survival in FA hearts because cardiac fibrosis and wall stress persisted even with omaveloxolone treatment. More studies are warranted to determine the cause of premature death in omaveloxolone\u2010treated FXN\u2010cKO female mice.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.124.038505","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T03:27:51Z","timestamp":1749698871000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":12,"title":["Omaveloxolone, But Not Dimethyl Fumarate, Improves Cardiac Function in Friedreich's Ataxia Mice With Severe Cardiomyopathy"],"prefix":"10.1161","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4743-2134","authenticated-orcid":false,"given":"Lili","family":"Salinas","sequence":"first","affiliation":[{"name":"University of California","place":["Davis, 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USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9499-8817","authenticated-orcid":false,"given":"Nipavan","family":"Chiamvimonvat","sequence":"additional","affiliation":[{"name":"University of California","place":["Davis, USA"]},{"name":"Northern California Health Care System","place":["Mather, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2563-4133","authenticated-orcid":false,"given":"Gino","family":"Cortopassi","sequence":"additional","affiliation":[{"name":"University of California","place":["Davis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0601-9816","authenticated-orcid":false,"given":"Elena N.","family":"Dedkova","sequence":"additional","affiliation":[{"name":"University of California","place":["Davis, USA"]},{"name":"California Northstate University","place":["Elk Grove, 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