Abstract
Methamphetamine (METH) is a commonly abused psychostimulant that can induce severe neurotoxicity. Cardiovascular injury caused by METH has recently gained increasing attention; however, the underlying mechanisms remain unclear. As autophagy has been shown to be associated with cell injury, the association between autophagy and METH-mediated cell apoptosis was investigated in the present study. METH treatment significantly increased the expression of two key autophagy proteins, i.e., Beclin-1 and LC3-II, in the cardiomyocyte cell line H9C2. Furthermore, according to western blot and flow cytometry analyses, METH contributed to cell injury and markedly enhanced cleaved-caspase 3 and PARP expression. In addition, the corresponding AKT-mTOR survival pathway axis was appeared deactivated. The autophagic activity was closely associated with METH-mediated cell injury because rapamycin, which is an autophagy inducer, markedly attenuated METH-induced cell injury, while 3-Methyladenine (3-MA), which is an autophagy inhibitor, and bafilomycinA1 (Baf-A1), which is a blocker of autophagosome-lysosome fusion, markedly exacerbated METH-induced cell injury. Notably, defective autophagosome-lysosome fusion might be partially involved in the METH-induced enhancement of LC3-II expression and cell injury. However, the underlying mechanisms require further investigation.
Keywords:
Autophagy; Cell injury; H9C2; Methamphetamine.
Copyright © 2018 Elsevier B.V. All rights reserved.
MeSH terms
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Animals
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Antibiotics, Antineoplastic / pharmacology
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Apoptosis / drug effects*
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Autophagosomes / drug effects
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Autophagosomes / enzymology
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Autophagosomes / metabolism
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Autophagy / drug effects*
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Beclin-1 / agonists
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Beclin-1 / genetics
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Beclin-1 / metabolism
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Caspase 3 / chemistry
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Caspase 3 / genetics
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Caspase 3 / metabolism
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Cell Survival / drug effects
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Central Nervous System Stimulants / agonists
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Central Nervous System Stimulants / antagonists & inhibitors
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Central Nervous System Stimulants / toxicity*
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation / drug effects*
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Green Fluorescent Proteins / chemistry
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Lysosomes / drug effects
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Lysosomes / enzymology
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Lysosomes / metabolism
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Macrolides / pharmacology
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Membrane Fusion / drug effects
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Methamphetamine / agonists
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Methamphetamine / antagonists & inhibitors
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Methamphetamine / toxicity*
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Microtubule-Associated Proteins / agonists
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Microtubule-Associated Proteins / chemistry
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Myocytes, Cardiac / cytology
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Myocytes, Cardiac / drug effects*
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Myocytes, Cardiac / metabolism
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Poly (ADP-Ribose) Polymerase-1 / chemistry
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Poly (ADP-Ribose) Polymerase-1 / genetics
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Poly (ADP-Ribose) Polymerase-1 / metabolism
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Rats
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / metabolism
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Sirolimus / pharmacology
Substances
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Antibiotics, Antineoplastic
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Beclin-1
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Becn1 protein, rat
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Central Nervous System Stimulants
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Enzyme Inhibitors
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LC3 protein, rat
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Macrolides
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Microtubule-Associated Proteins
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Recombinant Fusion Proteins
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Green Fluorescent Proteins
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Methamphetamine
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bafilomycin A1
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Parp1 protein, rat
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Poly (ADP-Ribose) Polymerase-1
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Casp3 protein, rat
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Caspase 3
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Sirolimus