title: Sphingosylphosphorylcholine protects cardiomyocytes against ischemic apoptosis via lipid raft/PTEN/Akt1/mTOR mediated autophagy.
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.
authors: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.
authors: Hong-Wei
authors: HW
authors: Yue
authors: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.
authors: Jing
authors: J
authors: Liu
authors: Department of Cardiology, Yantai Mountain Hospital, Yantai 264000, China.
authors: Ping-Ping
authors: PP
authors: Liu
authors: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.
authors: Wen-Jing
authors: WJ
authors: Li
authors: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.
authors: Fen
authors: F
authors: Chang
authors: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.
authors: Jun-Ying
authors: JY
authors: Miao
authors: Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China. Electronic address: jingzhao@sdu.edu.cn.
authors: Jing
authors: J
authors: Zhao
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D021962:Membrane Microdomains / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D000225:Adenine; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D048670:MAP Kinase Kinase 4; D008869:Microtubule-Associated Proteins; D048055:Mitogen-Activated Protein Kinase 8; D051059:PTEN Phosphohydrolase; D010750:Phosphoproteins; D010767:Phosphorylcholine; D051057:Proto-Oncogene Proteins c-akt; D011993:Recombinant Fusion Proteins; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D013110:Sphingosine; D058570:TOR Serine-Threonine Kinases; D047392:beta-Cyclodextrins; C499526:Eif4ebp1 protein, rat; C526109:Anxa3 protein, rat; C005356:sphingosine phosphorylcholine; C025946:3-methyladenine; C546842:MTOR protein, human; C494918:AKT1 protein, human; C487216:Pten protein, rat; C031215:betadex
keywords: Apoptosis; Autophagy; Cardiomyocyte; Lipid raft; Sphingosylphosphorylcholine (SPC)