title: The role of frataxin in doxorubicin-mediated cardiac hypertrophy.
abstract: Doxorubicin (DOX) is a highly effective anti-neoplastic agent; however, its cumulative dosing schedules are clinically limited by the development of cardiotoxicity. Previous studies have attributed the cause of DOX-mediated cardiotoxicity to mitochondrial iron accumulation and the ensuing reactive oxygen species (ROS) formation. The present study investigates the role of frataxin (FXN), a mitochondrial iron-sulfur biogenesis protein, and its role in development of DOX-mediated mitochondrial dysfunction. Athymic mice treated with DOX (5 mg/kg, 1 dose/wk with treatments, followed by 2-wk recovery) displayed left ventricular hypertrophy, as observed by impaired cardiac hemodynamic performance parameters. Furthermore, we also observed significant reduction in FXN expression in DOX-treated animals and H9C2 cardiomyoblast cell lines, resulting in increased mitochondrial iron accumulation and the ensuing ROS formation. This observation was paralleled in DOX-treated H9C2 cells by a significant reduction in the mitochondrial bioenergetics, as observed by the reduction of myocardial energy regulation. Surprisingly, similar results were observed in our FXN knockdown stable cell lines constructed by lentiviral technology using short hairpin RNA. To better understand the cardioprotective role of FXN against DOX, we constructed FXN overexpressing cardiomyoblasts, which displayed cardioprotection against mitochondrial iron accumulation, ROS formation, and reduction of mitochondrial bioenergetics. Lastly, our FXN overexpressing cardiomyoblasts were protected from DOX-mediated cardiac hypertrophy. Together, our findings reveal novel insights into the development of DOX-mediated cardiomyopathy.
authors.affiliation: Department of Drug, Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama;
authors.forename: Shravanthi
authors.initials: S
authors.lastname: Mouli
authors.affiliation: Department of Drug, Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama;
authors.forename: Gayani
authors.initials: G
authors.lastname: Nanayakkara
authors.affiliation: Department of Drug, Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama;
authors.forename: Abdullah
authors.initials: A
authors.lastname: AlAlasmari
authors.affiliation: Department of Drug, Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama;
authors.forename: Haitham
authors.initials: H
authors.lastname: Eldoumani
authors.affiliation: Department of Drug, Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama;
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Fu
authors.affiliation: Department of Drug, Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama;
authors.forename: Avery
authors.initials: A
authors.lastname: Berlin
authors.affiliation: Department of Drug, Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama;
authors.forename: Madhukar
authors.initials: M
authors.lastname: Lohani
authors.affiliation: Department of Drug, Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama;
authors.forename: Ben
authors.initials: B
authors.lastname: Nie
authors.affiliation: Department of Drug, Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama;
authors.forename: Robert D
authors.initials: RD
authors.lastname: Arnold
authors.affiliation: School of Kinesiology, Auburn University, Auburn, Alabama;
authors.forename: Andreas
authors.initials: A
authors.lastname: Kavazis
authors.affiliation: Department of Drug, Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama;
authors.forename: Forrest
authors.initials: F
authors.lastname: Smith
authors.affiliation: Auburn University MRI Research Center, Auburn, Alabama; and.
authors.forename: Ronald
authors.initials: R
authors.lastname: Beyers
authors.affiliation: Department of Electrical and Computer Engineering, Auburn University, Auburn, Alabama; Auburn University MRI Research Center, Auburn, Alabama; and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Denney
authors.affiliation: Department of Drug, Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama;
authors.forename: Muralikrishnan
authors.initials: M
authors.lastname: Dhanasekaran
authors.affiliation: Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama.
authors.forename: Juming
authors.initials: J
authors.lastname: Zhong
authors.affiliation: School of Kinesiology, Auburn University, Auburn, Alabama;
authors.forename: John
authors.initials: J
authors.lastname: Quindry
authors.affiliation: Department of Drug, Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama; rha0003@auburn.edu.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Amin
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism*; D066126:Cardiotoxicity; D002460:Cell Line; D002478:Cells, Cultured; D004317:Doxorubicin / Q000009:adverse effects*; D007501:Iron / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000096923:Frataxin
chemical_list: D004317:Doxorubicin; D007501:Iron; D033862:Iron-Binding Proteins; D017382:Reactive Oxygen Species; D000096923:Frataxin
keywords: anthracyclines; cardiomyopathy; frataxin; iron overload; mitochondrial damage; oxidative stress