Abstract
Autophagy, evoked by diverse stresses including myocardial ischemia/reperfusion (I/R), profoundly affects the development of heart failure. However, the specific molecular basis of autophagy remains to be elucidated. Here we report that sphingosylphosphorylcholine (SPC), a bioactive sphingolipid, significantly suppressed apoptosis and induced autophagy in cardiomyocytes. Blocking this SPC evoked autophagy by 3-methyladenine (3MA)-sensitized cardiomyocytes to serum deprivation-induced apoptosis. Subsequent studies revealed that SPC downregulated the phosphorylation of p70S6K and 4EBP1 (two substrates of mTOR) but enhanced that of JNK when inducing autophagy. We identified SPC as a switch for the activity of Akt1, a supposed upstream modulator of both mTOR and JNK. Furthermore, β-cyclodextrin, which destroys membrane cholesterol, abolished the SPC-reduced phosphorylation of both Akt and PTEN, thus inhibiting SPC-induced autophagy. In conclusion, SPC is a novel molecule protecting cardiomyocytes against apoptosis by promoting autophagy. The lipid raft/PTEN/Akt1/mTOR signal pathway is the underlying mechanism and might provide novel targets for cardiac failure therapy.
Keywords:
Apoptosis; Autophagy; Cardiomyocyte; Lipid raft; Sphingosylphosphorylcholine (SPC).
Copyright © 2015 Elsevier B.V. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenine / analogs & derivatives
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Adenine / pharmacology
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Animals
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Animals, Newborn
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Apoptosis / drug effects
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Autophagy / drug effects
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Gene Expression Regulation
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Intracellular Signaling Peptides and Proteins
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MAP Kinase Kinase 4 / genetics
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MAP Kinase Kinase 4 / metabolism
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Membrane Microdomains / chemistry
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Membrane Microdomains / drug effects*
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Membrane Microdomains / metabolism
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Mitogen-Activated Protein Kinase 8 / genetics
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Mitogen-Activated Protein Kinase 8 / 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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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / metabolism*
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Phosphorylcholine / analogs & derivatives*
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Phosphorylcholine / metabolism
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Phosphorylcholine / pharmacology
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Primary Cell Culture
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism*
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Rats
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Rats, Sprague-Dawley
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Ribosomal Protein S6 Kinases, 70-kDa / genetics
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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Signal Transduction
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Sphingosine / analogs & derivatives*
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Sphingosine / metabolism
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Sphingosine / pharmacology
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism*
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beta-Cyclodextrins / pharmacology
Substances
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Carrier Proteins
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Eif4ebp1 protein, rat
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Intracellular Signaling Peptides and Proteins
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LC3 protein, rat
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Microtubule-Associated Proteins
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Phosphoproteins
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Recombinant Fusion Proteins
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beta-Cyclodextrins
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sphingosine phosphorylcholine
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Phosphorylcholine
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3-methyladenine
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MTOR protein, human
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AKT1 protein, human
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Proto-Oncogene Proteins c-akt
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Ribosomal Protein S6 Kinases, 70-kDa
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TOR Serine-Threonine Kinases
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Mitogen-Activated Protein Kinase 8
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MAP Kinase Kinase 4
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PTEN Phosphohydrolase
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Pten protein, rat
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Adenine
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betadex
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Sphingosine