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DNA damage-inducible transcript 4 (DDIT4) mediates methamphetamine-induced autophagy and apoptosis through mTOR

Rui Chen1, Bin Wang2, Ling Chen2

  • 1Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China; Department of Forensic Medicine, Guangdong Medical University, Dongguan 523808, People's Republic of China.

Toxicology and Applied Pharmacology
|January 31, 2016
PubMed

Insights

DNA damage-inducible transcript 4 (DDIT4) plays a key role in methamphetamine-induced cardiotoxicity. Silencing DDIT4 protects heart cells from methamphetamine-induced autophagy and apoptosis via the mTOR pathway.

Area of Science:

  • Cardiovascular Biology
  • Molecular Toxicology
  • Cellular Signaling

Background:

  • Methamphetamine (METH) abuse can lead to severe cardiovascular damage.
  • DNA damage-inducible transcript 4 (DDIT4) is implicated in METH neurotoxicity.
  • The role of DDIT4 in METH-induced cardiotoxicity is currently unknown.

Purpose of the Study:

  • To investigate the role of DDIT4 in METH-induced cardiotoxicity.
  • To determine if DDIT4 mediates autophagy and apoptosis in cardiomyocytes exposed to METH.
  • To elucidate the involvement of the mTOR signaling pathway.

Main Methods:

  • Western blotting to assess DDIT4 protein expression and mTOR phosphorylation in cardiomyocytes and rat heart tissues.
  • Silencing DDIT4 expression using siRNA in cardiomyocytes.
  • Evaluating autophagy and apoptosis using fluorescence microscopy and TUNEL staining.
  • Utilizing rapamycin, an mTOR inhibitor, in conjunction with DDIT4 knockdown.

Main Results:

  • METH exposure increased DDIT4 expression and autophagy/apoptosis in cardiomyocytes, both in vitro and in vivo.
  • METH exposure decreased mTOR phosphorylation, indicating pathway activation.
  • Silencing DDIT4 normalized METH-induced increases in autophagy and apoptosis.
  • Rapamycin exacerbated METH-induced autophagy and apoptosis in DDIT4 knockdown cells.

Conclusions:

  • DDIT4 mediates METH-induced autophagy and apoptosis in cardiomyocytes.
  • The DDIT4-mediated cardiotoxicity involves the mTOR signaling pathway.
  • Targeting DDIT4 may offer a therapeutic strategy against METH cardiotoxicity.
Keywords:
ApoptosisAutophagyCardiotoxicityDDIT4 (DNA damage-inducible transcript 4)Methamphetamine

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