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Here, we examined the functional significance of myocardial ferritin heavy chain (FtH) in a model of acute myocardial infarction. We report that FtH deletion did not alter either the mitochondrial regulatory and surveillance pathways (fission and fusion) or mitochondrial bioenergetics in response to injury. Furthermore, deletion of myocardial FtH did not affect cardiac function, assessed by measurement of left ventricular ejection fraction, on days 1, 7, and 21 post injury. To identify the modulated pathways providing cardiomyocyte protection coincident with FtH deletion, we performed unbiased transcriptomic analysis. We found that following injury, FtH deletion was associated with upregulation of several genes with anti-ferroptotic properties, including heme oxygenase-1 (HO-1) and the cystine\/glutamate anti-porter (Slc7a11). These results suggested that HO-1 overexpression mitigates ferroptosis via upregulation of Slc7a11. Indeed, using transgenic mice with HO-1 overexpression, we demonstrate that overexpressed HO-1 is coupled with increased Slc7a11 expression. In conclusion, we demonstrate that following injury, myocardial FtH deletion leads to a compensatory upregulation in a number of anti-ferroptotic genes, including HO-1. Such HO-1 induction leads to overexpression of Slc7a11 and protects the heart against ischemia-reperfusion-mediated ferroptosis, preserves mitochondrial function, and overall function of the myocardium.<\/jats:p>","DOI":"10.3390\/ijms23158300","type":"journal-article","created":{"date-parts":[[2022,7,27]],"date-time":"2022-07-27T21:11:05Z","timestamp":1658956265000},"page":"8300","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Counteraction of Myocardial Ferritin Heavy Chain Deficiency by Heme Oxygenase-1"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1506-6419","authenticated-orcid":false,"given":"Sarah E.","family":"Machado","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daryll","family":"Spangler","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3824-0953","authenticated-orcid":false,"given":"Delores A.","family":"Stacks","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Darley-Usmar","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria A.","family":"Benavides","sequence":"additional","affiliation":[{"name":"Mitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2967-3490","authenticated-orcid":false,"given":"Min","family":"Xie","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7923-2645","authenticated-orcid":false,"given":"J\u00f3zsef","family":"Balla","sequence":"additional","affiliation":[{"name":"ELKH-UD Vascular Pathophysiology Research Group 11003, Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abolfazl","family":"Zarjou","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1161\/CIRCULATIONAHA.113.004042","article-title":"Temporal trends in ischemic heart disease mortality in 21 world regions, 1980 to 2010: The Global Burden of Disease 2010 study","volume":"129","author":"Moran","year":"2014","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"859","DOI":"10.2147\/CLEP.S317787","article-title":"Global Burden of Ischemic Heart Disease and Attributable Risk Factors, 1990\u20132017: A Secondary Analysis Based on the Global Burden of Disease Study 2017","volume":"13","author":"Wang","year":"2021","journal-title":"Clin. 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