title: Iron-overload injury and cardiomyopathy in acquired and genetic models is attenuated by resveratrol therapy.
abstract: Iron-overload cardiomyopathy is a prevalent cause of heart failure on a world-wide basis and is a major cause of mortality and morbidity in patients with secondary iron-overload and genetic hemochromatosis. We investigated the therapeutic effects of resveratrol in acquired and genetic models of iron-overload cardiomyopathy. Murine iron-overload models showed cardiac iron-overload, increased oxidative stress, altered Ca(2+) homeostasis and myocardial fibrosis resulting in heart disease. Iron-overload increased nuclear and acetylated levels of FOXO1 with corresponding inverse changes in SIRT1 levels in the heart corrected by resveratrol therapy. Resveratrol, reduced the pathological remodeling and improved cardiac function in murine models of acquired and genetic iron-overload at varying stages of iron-overload. Echocardiography and hemodynamic analysis revealed a complete normalization of iron-overload mediated diastolic and systolic dysfunction in response to resveratrol therapy. Myocardial SERCA2a levels were reduced in iron-overloaded hearts and resveratrol therapy restored SERCA2a levels and corrected altered Ca(2+) homeostasis. Iron-mediated pro-oxidant and pro-fibrotic effects in human and murine cardiomyocytes and cardiofibroblasts were suppressed by resveratrol which correlated with reduction in iron-induced myocardial oxidative stress and myocardial fibrosis. Resveratrol represents a clinically and economically feasible therapeutic intervention to reduce the global burden from iron-overload cardiomyopathy at early and chronic stages of iron-overload.
authors.affiliation: Division of Cardiology, Department of Medicine, New York.|Mazankowski Alberta Heart Institute, New York.
authors.forename: Subhash K
authors.initials: SK
authors.lastname: Das
authors.affiliation: Mazankowski Alberta Heart Institute, New York.|Department of Physiology, University of Alberta, New York.
authors.forename: Wang
authors.initials: W
authors.lastname: Wang
authors.affiliation: Division of Cardiology, Department of Medicine, New York.|Mazankowski Alberta Heart Institute, New York.
authors.forename: Pavel
authors.initials: P
authors.lastname: Zhabyeyev
authors.affiliation: Division of Cardiology, Department of Medicine, New York.|Mazankowski Alberta Heart Institute, New York.
authors.forename: Ratnadeep
authors.initials: R
authors.lastname: Basu
authors.affiliation: Mazankowski Alberta Heart Institute, New York.|Department of Physiology, University of Alberta, New York.
authors.forename: Brent
authors.initials: B
authors.lastname: McLean
authors.affiliation: Mazankowski Alberta Heart Institute, New York.|Department of Physiology, University of Alberta, New York.
authors.forename: Dong
authors.initials: D
authors.lastname: Fan
authors.affiliation: Division of Cardiology, Department of Medicine, New York.|Mazankowski Alberta Heart Institute, New York.
authors.forename: Nirmal
authors.initials: N
authors.lastname: Parajuli
authors.affiliation: Division of Cardiology, Department of Medicine, New York.|Mazankowski Alberta Heart Institute, New York.
authors.forename: Jessica
authors.initials: J
authors.lastname: DesAulniers
authors.affiliation: Division of Cardiology, Department of Medicine, New York.|Mazankowski Alberta Heart Institute, New York.
authors.forename: Vaibhav B
authors.initials: VB
authors.lastname: Patel
authors.affiliation: Mount Sinai School of Medicine, New York.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.affiliation: Departments of Pediatrics and Pharmacology, University of Alberta, Edmonton, Canada.
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.affiliation: Mazankowski Alberta Heart Institute, New York.|Department of Physiology, University of Alberta, New York.
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.affiliation: Division of Cardiology, Department of Medicine, New York.|Mazankowski Alberta Heart Institute, New York.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000150:complications* / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D058851:GPI-Linked Proteins; D015316:Genetic Therapy; D000071020:Hemochromatosis Protein; D006801:Humans; D019190:Iron Overload / Q000150:complications* / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008957:Models, Genetic; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D000077185:Resveratrol; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D058851:GPI-Linked Proteins; C504414:HJV protein, mouse; D000071020:Hemochromatosis Protein; D008565:Membrane Proteins; D016877:Oxidants; D013267:Stilbenes; D056564:Sirtuin 1; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000077185:Resveratrol