High-Density Lipoprotein–Associated Apolipoprotein M Limits Endothelial Inflammation by Delivering Sphingosine-1-Phosphate to the Sphingosine-1-Phosphate Receptor 1

Abstract

Objective-Plasma high-density lipoproteins (HDL) are potent antiatherogenic and anti-inflammatory particles. However, HDL particles are highly heterogenic in composition, and different HDL-mediated functions can be ascribed to different subclasses of HDL. Only a small HDL population contains apolipoprotein M (ApoM), which is the main plasma carrier of the bioactive lipid mediator sphingosine-1-phosphate (S1P). Vascular inflammation is modulated by S1P, but both proand anti-inflammatory roles have been ascribed to S1P. The goal of this study is to elucidate the role of ApoM and S1P in endothelial anti-inflammatory events related to HDL. Approach and Results-Aortic or brain human primary endothelial cells were challenged with tumor necrosis factor-α (TNF-α) as inflammatory stimuli. The presence of recombinant ApoM-bound S1P or ApoM-containing HDL reduced the abundance of adhesion molecules in the cell surface, whereas ApoM and ApoM-lacking HDL did not. Specifically, ApoM-bound S1P decreased vascular adhesion molecule-1 (VCAM-1) and E-selectin surface abundance but not intercellular adhesion molecule-1. Albumin, which is an alternative S1P carrier, was less efficient in inhibiting VCAM-1 than ApoM-bound S1P. The activation of the S1P receptor 1 was sufficient and required to promote anti-inflammation. Moreover, ApoM-bound S1P induced the rearrangement of the expression of S1P-related genes to counteract TNF-α. Functionally, HDL/ApoM/S1P limited monocyte adhesion to the endothelium and maintained endothelial barrier integrity under inflammatory conditions. Conclusions-ApoM-bound S1P is a key component of HDL and is responsible for several HDL-associated protective functions in the endothelium, including regulation of adhesion molecule abundance, leukocyte-endothelial adhesion, and endothelial barrier. Ruiz et al ApoM-Containing HDL Reduces Vascular Inflammation 119secretion and used by the mature ApoM protein to anchor to the phospholipid surface of HDL. 7,8 Five different membrane-bound G-protein-coupled S1P receptors (S1PRs) are known, and binding of S1P to the receptors activates multiple receptor-specific downstream signaling pathways. In this way, S1P is able to regulate several biological processes, such as immune cell trafficking, angiogenesis, endothelial cell migration, and endothelial barrier function. 9 The role of S1P in the regulation of vascular inflammation has been studied, and contradictory results have been obtained, for example, direct stimulation by S1P is reported to increase the abundance of adhesion molecules, whereas other studies [10][11][12] show that S1P inhibits tumor necrosis factor-α (TNF-α) induction of adhesion molecules, such as E-selectin, ICAM-1, or VCAM-1. 11,13The aim of this study is to characterize the role of S1P in the regulation of human endothelium inflammation taking into account that S1P is mostly bound to ApoM in plasma. Using recombinant human ApoM with or without bound S1P and isolated HDL containing or HDL lacking human ApoM (HDL +ApoM and HDL −ApoM , respectively), w...

Sphingosine 1‐Phosphate Receptor 1 Signaling Maintains Endothelial Cell Barrier Function and Protects Against Immune Complex–Induced Vascular Injury

“…We considered the possibility that local levels of S1P were elevated by platelets and/or EC release during RAR and obscured the effects of ApoM deficiency. At higher levels of S1P (~500nM), albumin and ApoM have been shown to be equally effective at reducing TNF-α induced VCAM-1 in ECs in vitro [32]. …”

Anti-Inflammatory Effects of HDL in Mice With Rheumatoid Arthritis Induced by Collagen

“…ApoM-bound S1P is a key component of HDL and is responsible for several HDL-associated protective functions (22). Many studies had shown that sphingosine-1-phosphate could attenuate organ injury and decrease the ability of the proinflammatory cytokine TNF-α to activate NF-κB (23, 24).…”

Upregulated Sphingosine 1-Phosphate Receptor 1 Expression in Human and Murine Atherosclerotic Plaques

“…Another study focused on the ApoM–S1P–S1PR1 signaling axis, which is proved to restrain the lymphocyte compartment and, subsequently, adaptive immune responses [25]. Specifically, in aortic primary endothelial cells, the anti-inflammatory effects of the ApoM-S1P complex are mediated by S1PR1 [26]. It is worth noting that patients with coronary artery disease have lower plasma S1P and HDL-S1P levels than controls [27].…”