Abstract 14194: Sphingosine 1-Phosphate Possesses the Carrier-dependent Effects on the Plasminogen Activator Inhibitor 1 Expression in Adipocytes

Introduction: Thrombosis-related diseases are still causing mortality and morbidity worldwide. Plasminogen activator inhibitor-1 (PAI-1) is one of the pro-coagulant factors and reported to be associated with cardiovascular diseases. Sphingosine 1-phosphate (S1P), a bioactive lysophospholipid mediator, has been demonstrated to increase the PAI-1 expression in adipocytes, however, many basic and clinical researches has suggested that S1P is an anti-atherosclerotic mediator. Hypothesis: S1P might possess different properties on the PAI-1 expression in adipocytes, depending on its carrier, since S1P is bound to apolipoprotein M (apoM) on HDL or albumin in plasma. Methods: First, we measured concentrations of S1P, apoM, and PAI-1 in the plasma of normal coronary artery, stable angina pectoris, and acute coronary syndrome subjects (n = 32, 71, and 38, respectively), and investigated the correlation among these molecules. Secondly, we treated 3T3L1 adipocytes with S1P, utilizing various vehicles, and compared the effects of S1P on the PAI-1 expression levels, as well as on the signal pathways involved in the induction of PAI-1 by S1P. Thirdly, we investigated the modulation of the PAI-1 level in mice infected with adenovirus coding apoM. Results: Among subjects with acute coronary syndrome, the plasma PAI-1 level was positively correlated with the S1P level, while not with the apoM level. In 3T3L1 adipocytes, S1P bound to apoM-rich vehicle induced PAI-1 expression to a lesser extent than S1P bound to the control vehicle, while S1P bound to apoM-depleted vehicle induced PAI-1 expression to a greater extent than S1P bound to the control vehicle. Moreover, adenoviral apoM overexpression in mice failed to modulate the plasma PAI-1 level and the expression of PAI-1 in adipose tissue. Conclusions: S1P bound to albumin, but not S1P bound to apoM, induces PAI-1 expression in adipocytes, indicating that S1P can exert different properties on the pathogenesis of vascular diseases, depending on its carrier.