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Male hemojuvelin (HJV) knockout (HJVKO) mice, which lack HJV, a bone morphogenetic co-receptor protein required for hepcidin expression and systemic iron homeostasis, were fed a high-iron diet starting at 4 weeks of age for a duration of 1 year. Aged HJVKO mice in response to iron overload showed increased myocardial iron deposition and mortality coupled with oxidative stress and myocardial fibrosis culminating in advanced iron-overload cardiomyopathy. In a parallel group, iron-overloaded HJVKO mice received resveratrol (240 mg\/day) at 9 months of age until 1 year of age. Echocardiography and invasive pressure\u2013volume (PV) loop analyses revealed a complete normalization of iron-overload mediated diastolic and systolic dysfunction in response to resveratrol therapy. In addition, myocardial sarcoplasmic reticulum Ca2+ ATPase (SERCa2a) levels were reduced in iron-overloaded hearts and resveratrol therapy restored SERCa2a levels and suppressed up-regulation of the sodium\u2013calcium exchanger (NCX1). Further, iron-mediated oxidative stress and myocardial fibrosis were suppressed by resveratrol treatment with concomitant activation of the p-Akt and p-AMP-activated protein kinase (AMPK) signaling pathways. A combination of ageing and high-iron diet in male HJVKO mice results in a valid preclinical model that recapitulates iron-overload cardiomyopathy in humans. Resveratrol therapy resulted in normalization of cardiac function demonstrating that resveratrol represents a feasible therapeutic intervention to reduce the burden of iron-overload cardiomyopathy.<\/jats:p>","DOI":"10.1042\/bsr20171302","type":"journal-article","created":{"date-parts":[[2017,12,6]],"date-time":"2017-12-06T01:11:15Z","timestamp":1512522675000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Advanced iron-overload cardiomyopathy in a genetic murine model is rescued by resveratrol therapy"],"prefix":"10.1042","volume":"38","author":[{"given":"Subhash\u00a0K.","family":"Das","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada"},{"name":"Mazankowski Alberta Heart Institute, Edmonton, Canada"},{"name":"Cardiovascular Research Centre, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavel","family":"Zhabyeyev","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada"},{"name":"Mazankowski Alberta Heart Institute, Edmonton, Canada"},{"name":"Cardiovascular Research Centre, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ratnadeep","family":"Basu","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada"},{"name":"Mazankowski Alberta Heart Institute, Edmonton, Canada"},{"name":"Cardiovascular Research Centre, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaibhav\u00a0B.","family":"Patel","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada"},{"name":"Mazankowski Alberta Heart Institute, Edmonton, Canada"},{"name":"Cardiovascular Research Centre, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason R.B.","family":"Dyck","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Centre, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada"},{"name":"Departments of Pediatrics and Pharmacology, University of Alberta, Edmonton, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zamaneh","family":"Kassiri","sequence":"additional","affiliation":[{"name":"Mazankowski Alberta Heart Institute, Edmonton, Canada"},{"name":"Cardiovascular Research Centre, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada"},{"name":"Department of Physiology, University of Alberta, Edmonton, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin\u00a0Y.","family":"Oudit","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada"},{"name":"Mazankowski Alberta Heart Institute, Edmonton, Canada"},{"name":"Cardiovascular Research Centre, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2018,1,10]]},"reference":[{"key":"2021111618515927800_B1","doi-asserted-by":"publisher","first-page":"1986","DOI":"10.1056\/NEJM199912233412607","article-title":"Disorders of iron metabolism","volume":"341","author":"Andrews","year":"1999","journal-title":"N. 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