HDL-associated lysosphingolipids inhibit NAD(P)H oxidase-dependent monocyte chemoattractant protein-1 production.
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.
Tölle
Markus
M
Charite - Campus Benjamin Franklin, Medizinische Klinik, Berlin, Germany.
Pawlak
Alicja
A
Schuchardt
Miriam
M
Kawamura
Akira
A
Tietge
Uwe J
UJ
Lorkowski
Stefan
S
Keul
Petra
P
Assmann
Gerd
G
Chun
Jerold
J
Levkau
Bodo
B
van der Giet
Markus
M
Nofer
Jerzy-Roch
JR
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
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