title: Visnagin protects against doxorubicin-induced cardiomyopathy through modulation of mitochondrial malate dehydrogenase.
abstract: Doxorubicin is a highly effective anticancer chemotherapy agent, but its use is limited by its cardiotoxicity. To develop a drug that prevents this toxicity, we established a doxorubicin-induced cardiomyopathy model in zebrafish that recapitulates the cardiomyocyte apoptosis and contractility decline observed in patients. Using this model, we screened 3000 compounds and found that visnagin (VIS) and diphenylurea (DPU) rescue the cardiac performance and circulatory defects caused by doxorubicin in zebrafish. VIS and DPU reduced doxorubicin-induced apoptosis in cultured cardiomyocytes and in vivo in zebrafish and mouse hearts. VIS treatment improved cardiac contractility in doxorubicin-treated mice. Further, VIS and DPU did not reduce the chemotherapeutic efficacy of doxorubicin in several cultured tumor lines or in zebrafish and mouse xenograft models. Using affinity chromatography, we found that VIS binds to mitochondrial malate dehydrogenase (MDH2), a key enzyme in the tricarboxylic acid cycle. As with VIS, treatment with the MDH2 inhibitors mebendazole, thyroxine, and iodine prevented doxorubicin cardiotoxicity, as did treatment with malate itself, suggesting that modulation of MDH2 activity is responsible for VIS' cardioprotective effects. Thus, VIS and DPU are potent cardioprotective compounds, and MDH2 is a previously undescribed, druggable target for doxorubicin-induced cardiomyopathy.
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA. Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA. Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Aarti
authors.initials: A
authors.lastname: Asnani
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Zou
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Bentley
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA. Broad Institute, Cambridge, MA 02142, USA.
authors.forename: You
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada. Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
authors.forename: Graham
authors.initials: G
authors.lastname: Dellaire
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA. Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Kumar S
authors.initials: KS
authors.lastname: Sarkar
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Dai
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Howard H
authors.initials: HH
authors.lastname: Chen
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Sosnovik
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Jordan T
authors.initials: JT
authors.lastname: Shin
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA. Howard Hughes Medical Institute.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
authors.affiliation: Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada. Department of Pediatrics, Izaak Walton Killam Health Centre, Halifax, Nova Scotia B3K 6R8, Canada.
authors.forename: Jason N
authors.initials: JN
authors.lastname: Berman
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chao
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA. Broad Institute, Cambridge, MA 02142, USA. rtpeterson@mgh.harvard.edu.
authors.forename: Randall T
authors.initials: RT
authors.lastname: Peterson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D017209:Apoptosis; D002224:Carbanilides / Q000494:pharmacology; D009202:Cardiomyopathies / Q000139:chemically induced / Q000188:drug therapy*; D002316:Cardiotonic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000009:adverse effects*; D006321:Heart / Q000187:drug effects*; D006801:Humans; D007666:Khellin / Q000494:pharmacology*; D008291:Malate Dehydrogenase / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000201:enzymology*; D009119:Muscle Contraction; D032383:Myocytes, Cardiac / Q000473:pathology; D009368:Neoplasm Transplantation; D015027:Zebrafish
chemical_list: D000970:Antineoplastic Agents; D002224:Carbanilides; D002316:Cardiotonic Agents; D007666:Khellin; D004317:Doxorubicin; D008291:Malate Dehydrogenase; C044999:visnagin