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

Abstract

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 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. Conclusion-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. (Arterioscler Thromb Vasc Biol. 2008;28:1542-1548)Key Words: HDL Ⅲ sphingosine-1-phosphate Ⅲ MCP-1 Ⅲ ROS Ⅲ NADPH-oxidase M onocyte infiltration into the vessel wall is an initial step in the formation of atherosclerotic lesion. 1,2 Monocyte chemoattractant protein-1 (MCP-1) is a key regulator of monocyte recruitment to sites of vascular inflammation. [2][3][4] In addition, MCP-1 induces several proinflammatory changes including secretion of cytokines and expression of adhesion molecules. 2-4 MCP-1 was detected in atherosclerotic lesion, and elevated levels of MCP-1 were encountered in acute coronary syndromes. 2-4 Animals genetically modified to lack MCP-1 or its receptor, CCR2, displayed reduced atherosclerotic lesions, whereas overexpression of MCP-1 in macrophages led to increased susceptibility to atherosclerosis. [2][3][4] Numerous studies documented an inverse relationship between high-density lipoprotein (HDL) levels and the progression of atherosclerosis and suggested that antiatherogenic effects of HDL are related to inflammation and its sequel. 5 For instance, HDL inhibits expression of adhesion molecules and reduces leukocyte homing to arterial endothelium. 5,6 Suppression of cytokine and chemokine production by HDL was observed after infusion of reconstituted HDL in animal models of inflammation. 7 The inverse relationship between HDL and acute phase proteins was repeatedly reported. 8 De...

The S1P1 receptor-selective agonist CYM-5442 reduces the severity of acute GVHD by inhibiting macrophage recruitment

“…45 An S1P 1 -selective agonist may act directly on macrophage proliferation and trafficking. [26][27][28][29]46 An in vivo proliferation assay demonstrated that CYM did not affect macrophage proliferation. Increasing amounts of data have indicated that the lower number of macrophages in the inflamed tissues of FTY720-treated mice could be an indirect effect of vascular permeability and monocyte recruitment.…”

“…29 We also monitored the changes of myeloid cells in the GVHD target organs with and without CYM treatment. As with the DCs shown in Figure 2, neutrophil numbers in the GVHD target organs were not affected by CYM treatment (data not shown).…”

“…S1P might also be involved in macrophage trafficking. 3,[26][27][28][29] FTY720 reduces macrophage infiltration into sites of inflammation in many inflammatory disease models. [30][31][32][33] The mechanism of action of FTY720 may involve its effects on endothelial cells to reduce monocyte migration.…”

Histone Deacetylase 3 Mediates Allergic Skin Inflammation by Regulating Expression of MCP1 Protein

“…It is plausible that expression of HDAC2 may be under post-translational control. Rac1 is necessary for MCP1 production in vascular smooth muscle cells (39). Rac1 promotes proteasomal degradation of p21 (40) and is responsible for ubiquitination of the SWI/SNF protein BAF60b (41).…”

From Menace to Marvel

“…Sphingosine-1-phosphate and sphingosylphosphorylcholine (see also the Figure) have been shown to exert direct antioxidative and antiinflammatory effects via inhibition of NADPH oxidase activity and monocyte chemoattractant protein 1 expression via the sphingosine-1-phosphate 3 receptor and scavenger receptor type B1. 9 In addition, sphingosine-1-phosphate and sphingosylphosphorylcholine have both been shown to activate eNOS via Akt-mediated phosphorylation of eNOS at 1177 serine, 10 leading to enhanced NO formation of the enzyme. 11 A lysosphingolipidand/or HDL-mediated downregulation of AT1R has not yet been described in either of these phenomena.…”