Visnagin protects against doxorubicin-induced cardiomyopathy through modulation of mitochondrial malate dehydrogenase

Yan Liu; Aarti Asnani; Lin Zou; Victoria L. Bentley; Min Yu; You Wang; Graham Dellaire; Kumar S. Sarkar; Matthew Dai; Howard H. Chen; David E. Sosnovik; Jordan T. Shin; Daniel A. Haber; Jason N. Berman; Wei Chao; Randall T. Peterson

doi:10.1126/scitranslmed.3010189

Research ArticleCARDIAC SIDE EFFECTS

Visnagin protects against doxorubicin-induced cardiomyopathy through modulation of mitochondrial malate dehydrogenase

Yan Liu¹,²,*,
Aarti Asnani¹,²,*,
Lin Zou³,
Victoria L. Bentley⁴,
Min Yu⁵,
You Wang¹,²,
Graham Dellaire⁴,⁶,
Kumar S. Sarkar¹,²,
Matthew Dai¹,
Howard H. Chen¹,⁷,
David E. Sosnovik¹,⁷,
Jordan T. Shin¹,
Daniel A. Haber⁵,⁸,
Jason N. Berman⁹,¹⁰,
Wei Chao³ and
Randall T. Peterson¹,²,†

¹Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
²Broad Institute, Cambridge, MA 02142, USA.
³Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
⁴Department of Pathology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
⁵Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
⁶Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
⁷Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
⁸Howard Hughes Medical Institute.
⁹Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.
¹⁰Department of Pediatrics, Izaak Walton Killam Health Centre, Halifax, Nova Scotia B3K 6R8, Canada.

↵†Corresponding author. E-mail: rtpeterson{at}mgh.harvard.edu

↵* These authors contributed equally to this work.

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Science Translational Medicine 10 Dec 2014:
Vol. 6, Issue 266, pp. 266ra170
DOI: 10.1126/scitranslmed.3010189

Yan Liu

1Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.

2Broad Institute, Cambridge, MA 02142, USA.

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Aarti Asnani

1Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.

2Broad Institute, Cambridge, MA 02142, USA.

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Lin Zou

3Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.

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Victoria L. Bentley

4Department of Pathology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.

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Min Yu

5Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.

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You Wang

1Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.

2Broad Institute, Cambridge, MA 02142, USA.

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Graham Dellaire

4Department of Pathology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.

6Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.

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Kumar S. Sarkar

1Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.

2Broad Institute, Cambridge, MA 02142, USA.

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Matthew Dai

1Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.

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Howard H. Chen

1Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.

7Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.

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David E. Sosnovik

1Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.

7Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.

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Jordan T. Shin

1Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.

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Daniel A. Haber

5Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.

8Howard Hughes Medical Institute.

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Jason N. Berman

9Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada.

10Department of Pediatrics, Izaak Walton Killam Health Centre, Halifax, Nova Scotia B3K 6R8, Canada.

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Wei Chao

3Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.

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Randall T. Peterson

1Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.

2Broad Institute, Cambridge, MA 02142, USA.

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For correspondence: rtpeterson@mgh.harvard.edu

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Taming the Red Devil

The cancer chemotherapy drug doxorubicin saves lives but its propensity to also inflict damage on the heart has earned it the nickname of the Red Devil. Liu et al. have now identified a compound that can prevent this drug-induced heart damage while leaving its cancer killing qualities intact. This agent, visnatin, was found among 3000 tested on a versatile piscine model, the zebrafish. After doxorubicin treatment, zebrafish hearts too suffer damage and visnagin protected them from injury. These salutary effects of visnagin were also apparent in mice, where it acts through mitochondrial malate dehydrogenase, a key metabolic enzyme. This or similar drugs may prove to be a valuable companion for doxorubicin, allowing it to acquire a less fiendish nickname.

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Visnagin protects against doxorubicin-induced cardiomyopathy through modulation of mitochondrial malate dehydrogenase

Taming the Red Devil

Science Translational Medicine

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