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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1542.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

HDL-Associated Lysosphingolipids Inhibit NAD(P)H Oxidase-Dependent Monocyte Chemoattractant Protein-1 Production

Markus Tölle; Alicja Pawlak; Miriam Schuchardt; Akira Kawamura; Uwe J. Tietge; Stefan Lorkowski; Petra Keul; Gerd Assmann; Jerold Chun; Bodo Levkau; Markus van der Giet; Jerzy-Roch Nofer

From the Charite - Campus Benjamin Franklin, Medizinische Klinik IV (M.T., M.S., U.J.T., M.v.d.G.), Berlin, Germany; Leibnitz-Institut für Arterioskleroseforschung an der Universität Münster (A.P., A.K., S.L., J.-R.N.), Münster, Germany; the Center for Liver, Digestive, and Metabolic Diseases (U.J.T.), University Medical Center Groningen, the Netherlands; Institut für Pathophysiologie im Zentrum für Innere Medizin (P.K., B.L.), Universität Essen, Germany; Assmann-Stiftung für Prävention (G.A.), Münster, Germany; the Department of Molecular Biology (J.C.), Scripps Research Institute, La Jolla, Calif; and Centrum für Laboratoriumsmedizin (J.-R.N.), Universitätsklinikum Münster, Münster, Germany.

Correspondence to Markus van der Giet, MD, Medizinische Klinik – SP Nephrologie, Charite – Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany. E-mail markus.vandergiet{at}charite.de

Objectives— High-density lipoprotein (HDL) levels are inversely proportional to the risk of atherosclerosis, but mechanisms of HDL atheroprotection remain unclear. Monocyte chemoatractant protein-1 (MCP-1) constitutes an early component of inflammatory response in atherosclerosis. Here we investigated the influence of HDL on MCP-1 production in vascular smooth muscle cells (VSMCs) and rat aortic explants.

Methods and Results— HDL inhibited the thrombin-induced production of MCP-1 in a concentration-dependent manner. The HDL-dependent inhibition of MCP-1 production was accompanied by the suppression of reactive oxygen species (ROS), which regulate the MCP-1 production in VSMCs. HDL inhibited NAD(P)H oxidase, the preponderant source of ROS in the vasculature, and prevented the activation of Rac1, which precedes NAD(P)H-oxidase activation. The HDL capacity to inhibit MCP-1 production, ROS generation, and NAD(P)H-oxidase activation was emulated by sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), two lysosphingolipids present in HDL, but not by apolipoprotein A-I. HDL-, S1P-, and SPC-induced inhibition of MCP-1 production was attenuated in VSMCs pretreated with VPC23019, an antagonist of lysosphingolipid receptors S1P₁ and S1P₃, but not by JTE013, an antagonist of S1P₂. In addition, HDL, S1P, and SPC failed to inhibit MCP1 production and ROS generation in aortas from S1P₃- and SR-B1-deficient mice.

Conclusion— HDL-associated lysosphingolipids inhibit NAD(P)H oxidase-dependent ROS generation and MCP-1 production in a process that requires coordinate signaling through S1P₃ and SR-B1 receptors.

HDL inhibits thrombin-induced production of monocyte chemoattractant protein-1 (MCP-1) in vascular smooth muscle cells and aortas. The reduced MCP-1 production is associated with inhibition of reactive oxygen species, NAD(P)H oxidase, and Rac-1, is not observed in aortas from S1P₃^–/– and SR-B1^–/– mice, and is emulated by HDL-associated sphingosine-1-phosphate and sphingosylphosphoryl-choline.

Key Words: HDL • sphingosine-1-phosphate • MCP-1 • ROS • NADPH-oxidase

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