Vehicle-dependent Effects of Sphingosine 1-phosphate on Plasminogen Activator Inhibitor-1 Expression

• Published in: Journal of Atherosclerosis and Thrombosis 2017/09/01, Vol.24(9), pp.954-969
• Main Authors: Takahashi, Chiharu, Kurano, Makoto, Nishikawa, Masako, Kano, Kuniyuki, Dohi, Tomotaka, Miyauchi, Katsumi, Daida, Hiroyuki, Shimizu, Tomo, Aoki, Junken, Yatomi, Yutaka
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; Acute Coronary Syndrome - blood; Adipocytes - metabolism; Angina, Stable - blood; Animals; Apolipoprotein M; Apolipoproteins M - blood; Human Umbilical Vein Endothelial Cells; Humans; Lipoproteins, HDL - blood; Lysophospholipids - administration & dosage; Lysophospholipids - blood; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; NF-kappa B - blood; Original; Plasminogen activator inhibitor 1; Plasminogen Activator Inhibitor 1 - blood; Platelet Activation; Protein Binding; Receptors, Lysosphingolipid - blood; Recombinant Proteins - blood; Serpin E2 - blood; Serum Albumin, Human - metabolism; Signal Transduction; Sphingosine - administration & dosage; Sphingosine - analogs & derivatives; Sphingosine - blood; Sphingosine 1-phosphate
• ISSN: 1340-3478; 1880-3873
• DOI: 10.5551/jat.37663

Aim: 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.Conclusion: 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.