Vehicle-dependent Effects of Sphingosine 1-phosphate on Plasminogen Activator Inhibitor-1 Expression.
OBJECTIVE
Sphingosine 1-phosphate (S1P) has been suggested to be a positive regulator of plasminogen activator inhibitor 1 (PAI-1) in adipocytes, while some studies are not consistent with this prothrombotic property of S1P. Since S1P is bound to apolipoprotein M (apoM) on HDL or to albumin in plasma, we compared the properties of these two forms on the PAI-1 induction.


METHODS
We investigated the associations of S1P, apoM, and PAI-1 concentrations in the plasma of normal coronary artery (NCA), stable angina pectoris (SAP), and acute coronary syndrome (ACS) subjects (n=32, 71, and 38, respectively). Then, we compared the effects of S1P with various vehicles on the PAI-1 expression in 3T3L1 adipocytes. We also investigated the modulation of the PAI-1 levels in mice infected with adenovirus coding apoM.


RESULTS
Among ACS subjects, the PAI-1 level was positively correlated with the S1P level, but not the apoM level. In adipocytes, S1P bound to an apoM-rich vehicle induced PAI-1 expression to a lesser extent than the control vehicle, while S1P bound to an apoM-depleted vehicle induced PAI-1 expression to a greater extent than the control vehicle in 3T3L1 adipocytes. Additionally, apoM overexpression in mice failed to modulate the plasma PAI-1 level and the adipose PAI-1 expression level. S1P bound to albumin increased PAI-1 expression through the S1P receptor 2-Rho/ROCK-NFκB pathway.


CONCLUSIONS
S1P bound to albumin, but not to apoM, induces PAI-1 expression in adipocytes, indicating that S1P can exert different properties on the pathogenesis of vascular diseases, depending on its vehicle.
Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo.|CREST, Japan Science and Technology Corporation (JST).
Chiharu
C
Takahashi
Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo.|CREST, Japan Science and Technology Corporation (JST).
Makoto
M
Kurano
Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo.|CREST, Japan Science and Technology Corporation (JST).
Masako
M
Nishikawa
CREST, Japan Science and Technology Corporation (JST).|Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University.
Kuniyuki
K
Kano
Department of Cardiovascular Medicine, Juntendo University School of Medicine.
Tomotaka
T
Dohi
Department of Cardiovascular Medicine, Juntendo University School of Medicine.
Katsumi
K
Miyauchi
Department of Cardiovascular Medicine, Juntendo University School of Medicine.
Hiroyuki
H
Daida
Tsukuba Research Institute, Research & Development Division, Sekisui Medical Co., Ltd.
Tomo
T
Shimizu
CREST, Japan Science and Technology Corporation (JST).|Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University.
Junken
J
Aoki
Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo.|CREST, Japan Science and Technology Corporation (JST).
Yutaka
Y
Yatomi
D041721:3T3-L1 Cells; D054058:Acute Coronary Syndrome / Q000097:blood; D017667:Adipocytes / Q000378:metabolism; D060050:Angina, Stable / Q000097:blood; D000818:Animals; D000075243:Apolipoproteins M / Q000097:blood; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood; D008246:Lysophospholipids / Q000008:administration & dosage* / Q000097:blood*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000097:blood; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood*; D015539:Platelet Activation; D011485:Protein Binding; D049349:Receptors, Lysosphingolipid / Q000097:blood; D011994:Recombinant Proteins / Q000097:blood; D058258:Serpin E2 / Q000097:blood; D000075462:Serum Albumin, Human / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood; D000081025:Sphingosine-1-Phosphate Receptors
C400523:APOM protein, human; C501623:ApoM protein, mouse; D000075243:Apolipoproteins M; D008075:Lipoproteins, HDL; D008246:Lysophospholipids; D016328:NF-kappa B; D017395:Plasminogen Activator Inhibitor 1; D049349:Receptors, Lysosphingolipid; D011994:Recombinant Proteins; C477522:S1PR2 protein, human; C051321:SERPINE1 protein, human; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; C060506:sphingosine 1-phosphate; D013110:Sphingosine; D000075462:Serum Albumin, Human
Apolipoprotein M; Plasminogen activator inhibitor 1; Sphingosine 1-phosphate