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Caspase-3 Activity in the Rat Amygdala Measured by Spectrofluorometry After Myocardial Infarction
Published on: January 12, 2016
MDMA induces cardiac contractile dysfunction through autophagy upregulation and lysosome destabilization in rats
Kaori Shintani-ishida1, Kanju Saka1, Koji Yamaguchi2
1Department of Forensic Medicine, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
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 (20mg/kg) or saline. Left ventricular (LV) echocardiography and LV pressure measurement demonstrated reduction of LV systolic contractility 24h 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.
Insights
3,4-methylenedioxymethylamphetamine (MDMA) cardiotoxicity involves autophagy-lysosomal pathway activation, leading to lysosome destabilization and myofibril damage. This results in reduced cardiac contractility and systolic dysfunction in rats.
Area of Science:
- Cardiology
- Toxicology
- Cell Biology
Background:
- The cardiotoxic mechanisms of 3,4-methylenedioxymethylamphetamine (MDMA, "ecstasy") are not fully understood.
- Autophagy's role in cardiac function varies, but its involvement in MDMA cardiotoxicity remains unknown.
Purpose of the Study:
- To investigate the mechanism of autophagy in MDMA-induced cardiac contractile dysfunction.
- To elucidate the role of the autophagy-lysosomal pathway in MDMA cardiotoxicity.
Main Methods:
- Rats were administered MDMA or saline, followed by echocardiography and LV pressure measurements.
- Western blot and electron microscopy were used to analyze autophagy markers, lysosomal enzymes, and myofibril damage.
- Autophagic and lysosomal inhibitors were employed to assess their impact on MDMA-induced dysfunction.
Main Results:
- MDMA administration reduced LV systolic contractility and induced autophagic vacuole formation in cardiomyocytes.
- MDMA activated the AMPK-mTOR pathway, enhancing autophagosome formation but impairing clearance.
- Lysosomal cathepsins were released, degrading cardiac troponin I and damaging myofibrils, which was ameliorated by inhibitors.
Conclusions:
- MDMA triggers lysosome destabilization via the autophagy-lysosomal pathway.
- Released lysosomal proteases contribute to myofibril damage and LV systolic dysfunction.
- Targeting the autophagy-lysosomal pathway may offer therapeutic potential for MDMA cardiotoxicity.
