title: High density lipoprotein (HDL)-associated sphingosine 1-phosphate (S1P) inhibits macrophage apoptosis by stimulating STAT3 activity and survivin expression.
abstract: Macrophage apoptosis is critically involved in atherosclerosis. We here examined the effect of anti-atherogenic high density lipoprotein (HDL) and its component sphingosine-1-phosphate (S1P) on apoptosis in RAW264.7 murine macrophages.
  
  
  
  Mitochondrial or endoplasmic reticulum-dependent apoptosis was induced by exposure of macrophages to etoposide or thapsigargin/fukoidan, respectively.
  
  
  
  Cell death induced by these compounds was inhibited by S1P as inferred from reduced annexin V binding, TUNEL staining, and caspase 3, 9 and 12 activities. S1P induced expression of the inhibitor of apoptosis protein (IAP) family proteins cIAP1, cIAP2 and survivin, but only the inhibitor of survivin expression YM155 and not the cIAP1/2 blocker GDC0152 reversed the inhibitory effect of S1P on apoptosis. Moreover, S1P activated signal transducer and activator of transcription 3 (STAT3) and Janus kinase 2 (JAK2) and the stimulatory effect of S1P on survivin expression and inhibitory effects on apoptosis were attenuated by STAT3 or JAK2 inhibitors, S3I-201 or AG490, respectively. The effects of S1P on STAT3 activation, survivin expression and macrophage apoptosis were emulated by HDL, HDL lipids, and apolipoprotein (apo) M-containing HDL, but not by apoA-I or HDL deprived of S1P or apoM. In addition, JTE013 and CAY10444, S1P receptor 2 and 3 antagonists, respectively, compromised the S1P and HDL capacities to stimulate STAT3 activation and survivin expression, and to inhibit apoptosis.
  
  
  
  HDL-associated S1P inhibits macrophage apoptosis by stimulating STAT3 activity and survivin expression. The suppression of macrophage apoptosis may represent a novel mechanism utilized by HDL to exert its anti-atherogenic effects.
authors.affiliation: Center for Laboratory Medicine, University Hospital Münster, Germany.
authors.forename: Renata
authors.initials: R
authors.lastname: Feuerborn
authors.affiliation: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Susen
authors.initials: S
authors.lastname: Becker
authors.affiliation: Department of Neuroscience - Unit of Pharmacology, University of Parma, Parma, Italy; Department of Biomedical, Metabolic and Neural Sciences - Unit of Endocrinology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Potì
authors.affiliation: Center for Laboratory Medicine, University Hospital Münster, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Nagel
authors.affiliation: Experimental and Clinical Haemostasis, Department of Anaesthesiology and Intensive Care, University Hospital Münster, Münster, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Brodde
authors.affiliation: Center for Laboratory Medicine, University Hospital Münster, Germany.
authors.forename: Harmut
authors.initials: H
authors.lastname: Schmidt
authors.affiliation: Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Christina
authors.initials: C
authors.lastname: Christoffersen
authors.affiliation: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Ceglarek
authors.affiliation: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Burkhardt
authors.affiliation: Center for Laboratory Medicine, University Hospital Münster, Germany. Electronic address: nofer@uni-muenster.de.
authors.forename: Jerzy-Roch
authors.initials: JR
authors.lastname: Nofer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005047:Etoposide / Q000633:toxicity*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000494:pharmacology*; D008246:Lysophospholipids / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000067996:RAW 264.7 Cells; D012097:Repressor Proteins / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077022:Survivin; D019284:Thapsigargin / Q000633:toxicity*; D013997:Time Factors
chemical_list: D051017:Apoptosis Regulatory Proteins; C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D008075:Lipoproteins, HDL; D008246:Lysophospholipids; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D000077022:Survivin; C060506:sphingosine 1-phosphate; D019284:Thapsigargin; D005047:Etoposide; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D013110:Sphingosine
keywords: Apoptosis; Atherosclerosis; High density lipoproteins (HDL); Macrophage; Sphingosine-1-phosphate (S1P)