MDMA induces cardiac contractile dysfunction through autophagy upregulation and lysosome destabilization in rats

Kaori Shintani-Ishida, Kanju Saka, Koji Yamaguchi, Makiko Hayashida, Hisashi Nagai, Genzou Takemura, Ken ichi Yoshida

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

The underlying mechanisms of cardiotoxicity of 3,4-methylenedioxymethylamphetamine (MDMA, "ecstasy") abuse are unclear. Autophagy exerts either adaptive or maladaptive effects on cardiac function in various pathological settings, but nothing is known on the role of autophagy in the MDMA cardiotoxicity. Here, we investigated the mechanism through which autophagy may be involved in MDMA-induced cardiac contractile dysfunction. Rats were injected intraperitoneally with MDMA (20. mg/kg) or saline. Left ventricular (LV) echocardiography and LV pressure measurement demonstrated reduction of LV systolic contractility 24. h after MDMA administration. Western blot analysis showed a time-dependent increase in the levels of microtubule-associated protein light chain 3-II (LC3-II) and cathepsin-D after MDMA administration. Electron microscopy showed the presence of autophagic vacuoles in cardiomyocytes. MDMA upregulated phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) at Thr172, mammalian target of rapamycin (mTOR) at Thr2446, Raptor at Ser792, and Unc51-like kinase (ULK1) at Ser555, suggesting activation of autophagy through the AMPK-mTOR pathway. The effects of autophagic inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) on LC3-II levels indicated that MDMA enhanced autophagosome formation, but attenuated autophagosome clearance. MDMA also induced release of cathepsins into cytosol, and western blotting and electron microscopy showed cardiac troponin I (cTnI) degradation and myofibril damage, respectively. 3-MA, CQ, and a lysosomal inhibitor, E64c, inhibited cTnI proteolysis and improved contractile dysfunction after MDMA administration. In conclusion, MDMA causes lysosome destabilization following activation of the autophagy-lysosomal pathway, through which released lysosomal proteases damage myofibrils and induce LV systolic dysfunction in rat heart.

Original languageEnglish
Pages (from-to)691-700
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1842
Issue number5
DOIs
Publication statusPublished - 2014 May
Externally publishedYes

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N-Methyl-3,4-methylenedioxyamphetamine
Autophagy
Lysosomes
Up-Regulation
Troponin I
Myofibrils
Chloroquine
Sirolimus
Adenosine Monophosphate
Protein Kinases
Electron Microscopy
Western Blotting
Raptors
Light
Cathepsins
Cathepsin D
Microtubule-Associated Proteins
Left Ventricular Dysfunction
Ventricular Pressure
Vacuoles

Keywords

  • Autophagy
  • Cardiac contractile dysfunction
  • Cathepsin
  • Lysosome
  • MDMA

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine

Cite this

MDMA induces cardiac contractile dysfunction through autophagy upregulation and lysosome destabilization in rats. / Shintani-Ishida, Kaori; Saka, Kanju; Yamaguchi, Koji; Hayashida, Makiko; Nagai, Hisashi; Takemura, Genzou; Yoshida, Ken ichi.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1842, No. 5, 05.2014, p. 691-700.

Research output: Contribution to journalArticle

Shintani-Ishida, Kaori ; Saka, Kanju ; Yamaguchi, Koji ; Hayashida, Makiko ; Nagai, Hisashi ; Takemura, Genzou ; Yoshida, Ken ichi. / MDMA induces cardiac contractile dysfunction through autophagy upregulation and lysosome destabilization in rats. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2014 ; Vol. 1842, No. 5. pp. 691-700.
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