Caloric restriction mimetic 2-deoxyglucose antagonizes doxorubicin-induced cardiomyocyte death by multiple mechanisms

Kai Chen, Xianmin Xu, Satoru Kobayashi, Derek Timm, Tyler Jepperson, Qiangrong Liang

Research output: Contribution to journalArticle

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Abstract

Caloric restriction (CR) is a dietary intervention known to enhance cardiovascular health. The glucose analog 2-deoxy-D-glucose (2-DG) mimics CR effects in several animal models. However, whether 2-DG is beneficial to the heart remains obscure. Here, we tested the ability of 2-DG to reduce cardiomyocyte death triggered by doxorubicin (DOX, 1 μM), an antitumor drug that can cause heart failure. Treatment of neonatal rat cardiomyocytes with 0.5 mM 2-DG dramatically suppressed DOX cytotoxicity as indicated by a decreased number of cells that stained positive for propidium iodide and reduced apoptotic markers. 2-DG decreased intracellular ATP levels by 17.9%, but it prevented DOX-induced severe depletion of ATP, which may contribute to 2-DG-mediated cytoprotection. Also, 2-DG increased the activity of AMP-activated protein kinase (AMPK). Blocking AMPK signaling with compound C or small interfering RNA-mediated knockdown of the catalytic subunit markedly attenuated the protective effects of 2-DG. Conversely, AMPK activation by pharmacological or genetic approach reduced DOX cardiotoxicity but did not produce additive effects when used together with 2-DG. In addition, 2-DG induced autophagy, a cellular degradation pathway whose activation could be either protective or detrimental depending on the context. Paradoxically, despite its ability to activate autophagy, 2-DG prevented DOX-induced detrimental autophagy. Together, these results suggest that the CR mimetic 2-DG can antagonize DOX-induced cardiomyocyte death, which is mediated through multiple mechanisms, including the preservation of ATP content, the activation of AMPK, and the inhibition of autophagy.

Original languageEnglish (US)
Pages (from-to)21993-22006
Number of pages14
JournalJournal of Biological Chemistry
Volume286
Issue number25
DOIs
StatePublished - Jun 24 2011

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Caloric Restriction
Deoxyglucose
Cardiac Myocytes
Doxorubicin
AMP-Activated Protein Kinases
Autophagy
Adenosine Triphosphate
Chemical activation
Cytoprotection
Propidium
Cytotoxicity
Antineoplastic Agents
Small Interfering RNA
Rats
Catalytic Domain
Animals
Animal Models
Heart Failure
Cell Count

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Caloric restriction mimetic 2-deoxyglucose antagonizes doxorubicin-induced cardiomyocyte death by multiple mechanisms. / Chen, Kai; Xu, Xianmin; Kobayashi, Satoru; Timm, Derek; Jepperson, Tyler; Liang, Qiangrong.

In: Journal of Biological Chemistry, Vol. 286, No. 25, 24.06.2011, p. 21993-22006.

Research output: Contribution to journalArticle

Chen, Kai ; Xu, Xianmin ; Kobayashi, Satoru ; Timm, Derek ; Jepperson, Tyler ; Liang, Qiangrong. / Caloric restriction mimetic 2-deoxyglucose antagonizes doxorubicin-induced cardiomyocyte death by multiple mechanisms. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 25. pp. 21993-22006.
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