title: Early biomarkers of doxorubicin-induced heart injury in a mouse model.
abstract: Cardiac troponins, which are used as myocardial injury markers, are released in plasma only after tissue damage has occurred. Therefore, there is a need for identification of biomarkers of earlier events in cardiac injury to limit the extent of damage. To accomplish this, expression profiling of 1179 unique microRNAs (miRNAs) was performed in a chronic cardiotoxicity mouse model developed in our laboratory. Male B6C3F1 mice were injected intravenously with 3mg/kg doxorubicin (DOX; an anti-cancer drug), or saline once a week for 2, 3, 4, 6, and 8weeks, resulting in cumulative DOX doses of 6, 9, 12, 18, and 24mg/kg, respectively. Mice were euthanized a week after the last dose. Cardiac injury was evidenced in mice exposed to 18mg/kg and higher cumulative DOX dose whereas examination of hearts by light microscopy revealed cardiac lesions at 24mg/kg DOX. Also, 24 miRNAs were differentially expressed in mouse hearts, with the expression of 1, 1, 2, 8, and 21 miRNAs altered at 6, 9, 12, 18, and 24mg/kg DOX, respectively. A pro-apoptotic miR-34a was the only miRNA that was up-regulated at all cumulative DOX doses and showed a significant dose-related response. Up-regulation of miR-34a at 6mg/kg DOX may suggest apoptosis as an early molecular change in the hearts of DOX-treated mice. At 12mg/kg DOX, up-regulation of miR-34a was associated with down-regulation of hypertrophy-related miR-150; changes observed before cardiac injury. These findings may lead to the development of biomarkers of earlier events in DOX-induced cardiotoxicity that occur before the release of cardiac troponins.
authors.affiliation: Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA. Electronic address: varsha.desai@fda.hhs.gov.
authors.forename: Varsha G
authors.initials: VG
authors.lastname: Desai
authors.affiliation: Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: C Kwekel
authors.affiliation: Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: Vikrant
authors.initials: V
authors.lastname: Vijay
authors.affiliation: Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Moland
authors.affiliation: Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, The National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20850-9734, USA.
authors.forename: Eugene H
authors.initials: EH
authors.lastname: Herman
authors.affiliation: Department of Mathematics, Korea University, Sejong, Chungnam 339-700, Republic of Korea.
authors.forename: Taewon
authors.initials: T
authors.lastname: Lee
authors.affiliation: Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Han
authors.affiliation: Office of Scientific Coordination, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: Sherry M
authors.initials: SM
authors.lastname: Lewis
authors.affiliation: Toxicologic Pathology Associates, National Center for Toxicological Research, Jefferson, AR 72079, USA.
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Davis
authors.affiliation: Toxicologic Pathology Associates, National Center for Toxicological Research, Jefferson, AR 72079, USA.
authors.forename: Levan
authors.initials: L
authors.lastname: Muskhelishvili
authors.affiliation: Arkansas Heart Hospital, Little Rock, AR 72211, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Kerr
authors.affiliation: Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Fuscoe
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic; D017209:Apoptosis / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004195:Disease Models, Animal; D004317:Doxorubicin; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005819:Genetic Markers; D006331:Heart Diseases / Q000097:blood / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D006657:Histones / Q000378:metabolism; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D020107:Troponin T / Q000097:blood
chemical_list: D000903:Antibiotics, Antineoplastic; D005819:Genetic Markers; D006657:Histones; D035683:MicroRNAs; D020107:Troponin T; C475961:gamma-H2AX protein, mouse; D004317:Doxorubicin
keywords: Biomarker; Doxorubicin; Heart; MicroRNA profiling; Mouse