title: HDL-associated lysosphingolipids inhibit NAD(P)H oxidase-dependent monocyte chemoattractant protein-1 production.
abstract: OBJECTIVE
  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.
  
  
  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 S1P(1) and S1P(3), but not by JTE013, an antagonist of S1P(2). In addition, HDL, S1P, and SPC failed to inhibit MCP1 production and ROS generation in aortas from S1P(3)- and SR-B1-deficient mice.
  
  
  CONCLUSIONS
  HDL-associated lysosphingolipids inhibit NAD(P)H oxidase-dependent ROS generation and MCP-1 production in a process that requires coordinate signaling through S1P(3) and SR-B1 receptors.
authors.affiliation: Charite - Campus Benjamin Franklin, Medizinische Klinik, Berlin, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Tölle
authors.forename: Alicja
authors.initials: A
authors.lastname: Pawlak
authors.forename: Miriam
authors.initials: M
authors.lastname: Schuchardt
authors.forename: Akira
authors.initials: A
authors.lastname: Kawamura
authors.forename: Uwe J
authors.initials: UJ
authors.lastname: Tietge
authors.forename: Stefan
authors.initials: S
authors.lastname: Lorkowski
authors.forename: Petra
authors.initials: P
authors.lastname: Keul
authors.forename: Gerd
authors.initials: G
authors.lastname: Assmann
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.forename: Bodo
authors.initials: B
authors.lastname: Levkau
authors.forename: Markus
authors.initials: M
authors.lastname: van der Giet
authors.forename: Jerzy-Roch
authors.initials: JR
authors.lastname: Nofer
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000502:physiology; D008246:Lysophospholipids / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D019255:NADPH Oxidases / Q000502:physiology; D051381:Rats; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000502:physiology; D051122:Scavenger Receptors, Class B; D013107:Sphingolipids / Q000737:chemistry / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000502:physiology; D000081025:Sphingosine-1-Phosphate Receptors
chemical_list: C491768:Ccl2 protein, mouse; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D008075:Lipoproteins, HDL; D008246:Lysophospholipids; D017382:Reactive Oxygen Species; D049349:Receptors, Lysosphingolipid; C501285:S1pr3 protein, mouse; C454739:Scarb1 protein, mouse; C495125:Scarb1 protein, rat; D051122:Scavenger Receptors, Class B; D013107:Sphingolipids; D000081025:Sphingosine-1-Phosphate Receptors; C060506:sphingosine 1-phosphate; D019255:NADPH Oxidases; D013110:Sphingosine