HDL-associated ApoM is anti-apoptotic by delivering sphingosine 1-phosphate to S1P1 & S1P3 receptors on vascular endothelium.
BACKGROUND
High-density Lipoprotein (HDL) attenuates endothelial cell apoptosis induced by different cell-death stimuli such as oxidation or growth factor deprivation. HDL is the main plasma carrier of the bioactive lipid sphingosine 1-phosphate (S1P), which it is a signaling molecule that promotes cell survival in response to several apoptotic stimuli. In HDL, S1P is bound to Apolipoprotein M (ApoM), a Lipocalin that is only present in around 5% of the HDL particles. The goal of this study is to characterize ApoM-bound S1P role in endothelial apoptosis protection and the signaling pathways involved.


METHODS
Human umbilical vein endothelial cells (HUVEC) cultures were switched to serum/grow factor deprivation medium to induce apoptosis and the effect caused by the addition of ApoM and S1P analyzed.


RESULTS
The addition of HDL+ApoMor recombinant ApoM-bound S1P promoted cell viability and blocked apoptosis, whereas HDL-ApoMhad no protective effect. Remarkably, S1P exerted a more potent anti-apoptotic effect when carried by ApoM as compared to albumin, or when added as free molecule. Mechanistically, cooperation between S1P1 and S1P3 was required for the HDL/ApoM/S1P-mediated anti-apoptotic ability. Furthermore, AKT and ERK phosphorylation was also necessary to achieve the anti-apoptotic effect of the HDL/ApoM/S1P complex.


CONCLUSIONS
Altogether, our results indicate that ApoM and S1P are key elements of the anti-apoptotic activity of HDL and promote optimal endothelial function.
Department of Translational Medicine, Skåne University Hospital, Lund University, Malmö, Sweden. mario.ruiz_garcia@med.lu.se.|Department of Translational Medicine, Clinical Chemistry, Wallenberg Laboratory, Lund University, Inga Marie Nilssons gata 53, SE-20502, Malmö, Sweden. mario.ruiz_garcia@med.lu.se.
Mario
M
Ruiz
Department of Translational Medicine, Skåne University Hospital, Lund University, Malmö, Sweden.
Hiromi
H
Okada
Department of Translational Medicine, Skåne University Hospital, Lund University, Malmö, Sweden.
Björn
B
Dahlbäck
D001053:Apolipoproteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000075243:Apolipoproteins M; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003470:Culture Media / Q000737:chemistry; D015870:Gene Expression; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008075:Lipoproteins, HDL / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008246:Lysophospholipids / Q000378:metabolism* / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D012709:Serum Albumin / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
C400523:APOM protein, human; D001053:Apolipoproteins; D000075243:Apolipoproteins M; D003470:Culture Media; D054834:Lipocalins; D008075:Lipoproteins, HDL; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; D012709:Serum Albumin; C060506:sphingosine 1-phosphate; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D013110:Sphingosine
ApoM; Apoptosis; Endothelial cells; HDL; Lipocalins; Sphingosine 1-phospate