{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T16:23:05Z","timestamp":1790871785660,"version":"4.1.0"},"reference-count":33,"publisher":"American Society of Hematology","issue":"6","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,2,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Sickle cell disease (SCD) is characterized by increased hemolysis, which results in plasma heme overload and ultimately cardiovascular complications. Here, we hypothesized that increased heme in SCD causes upregulation of heme oxygenase 1 (Hmox1), which consequently drives cardiomyopathy through ferroptosis, an iron-dependent non-apoptotic form of cell death. First, we demonstrated that the Townes SCD mice had higher levels of hemopexin-free heme in the serum and increased cardiomyopathy, which was corrected by hemopexin supplementation. Cardiomyopathy in SCD mice was associated with upregulation of cardiac Hmox1, and inhibition or induction of Hmox1 improved or worsened cardiac damage, respectively. Because free iron, a product of heme degradation through Hmox1, has been implicated in toxicities including ferroptosis, we evaluated the downstream effects of elevated heme in SCD. Consistent with Hmox1 upregulation and iron overload, levels of lipid peroxidation and ferroptotic markers increased in SCD mice, which were corrected by hemopexin administration. Moreover, ferroptosis inhibitors decreased cardiomyopathy, whereas a ferroptosis inducer erastin exacerbated cardiac damage in SCD and induced cardiac ferroptosis in nonsickling mice. Finally, inhibition or induction of Hmox1 decreased or increased cardiac ferroptosis in SCD mice, respectively. Together, our results identify ferroptosis as a key mechanism of cardiomyopathy in SCD.<\/jats:p>","DOI":"10.1182\/blood.2020008455","type":"journal-article","created":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T15:23:33Z","timestamp":1628868213000},"page":"936-941","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":178,"title":["Excess heme upregulates heme oxygenase 1 and promotes cardiac ferroptosis in mice with sickle cell disease"],"prefix":"10.1182","volume":"139","author":[{"given":"Archita Venugopal","family":"Menon","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Northeastern University, Boston, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7962-3096","authenticated-orcid":false,"given":"Jing","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanting Phoebe","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Northeastern University, Boston, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingxue","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Biomedical & Nutritional Sciences, University of Massachusetts Lowell, Lowell, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seungjeong","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Northeastern University, Boston, MA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aarti","family":"Asnani","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonghan","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Northeastern University, Boston, MA;"},{"name":"Department of Biomedical & Nutritional Sciences, University of Massachusetts Lowell, Lowell, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"23","key":"2022021016291475200_B1","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1182\/blood.V126.23.975.975","article-title":"Heme concentration as a biomarker of sickle\u00a0cell disease severity: its role in steady-state and in crisis patients","volume":"126","author":"Carvalho","year":"2015","journal-title":"Blood."},{"issue":"4","key":"2022021016291475200_B2","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1182\/blood-2015-08-663245","article-title":"Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease","volume":"127","author":"Vinchi","year":"2016","journal-title":"Blood."},{"issue":"12","key":"2022021016291475200_B3","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1161\/CIRCULATIONAHA.112.130179","article-title":"Hemopexin therapy improves cardiovascular function by preventing heme-induced endothelial toxicity in mouse models of hemolytic diseases","volume":"127","author":"Vinchi","year":"2013","journal-title":"Circulation."},{"issue":"23","key":"2022021016291475200_B4","doi-asserted-by":"crossref","first-page":"6388","DOI":"10.1016\/S0021-9258(18)63477-5","article-title":"Microsomal heme oxygenase. 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