Atheroprotective Effects of High-Density Lipoprotein-Associated Lysosphingolipids
Section snippets
Discovery of Lysosphingolipids Associated With HDL
HDL is structurally a heterogeneous class of lipoproteins. The bulk of HDL consists of spherical particles that contain a core of water-insoluble cholesterol ester and triacylglycerols and a hydrophilic surface layer formed by amphipathic phospholipids, free cholesterol, and apolipoproteins. Apolipoproteins (apo) A-I and apo A-II are quantitatively the most important protein constituents of HDL. They are not only involved in determining HDL structure but also exert several biological actions.
Lysosphingolipids in Plasma and Lipoproteins
S1P and SPC are important bioactive lipids generated upon cell activation from membrane phospholipids as a part of sphingomyelin cycle (Figure 1). S1P is synthesized from sphingosine by sphingosine kinase and stored primarily in platelets, as these cells lack the S1P lyase, which catalyzes S1P degradation (Spiegel and Milstein 2003). SPC was shown to be formed from sphingomyelin by the enzyme sphingomyelin deacylase and degraded to S1P by serum lysophospholipase (D Higuchi et al. 2000, Clair et
HDL-Associated Lysophospholipids and Endothelial Reparatory Processes
Traditional hypotheses of atherogenesis suggested that injury of vascular endothelium followed by endothelial cell death and denudation of intima is critical for the development of atherosclerosis. The sites where plaques develop are associated with increased endothelial cell turnover rates owing to an increased rate of apoptosis and reparatory processes such as cell proliferation. Increased apoptosis may be due to a variety of systemic factors: for example, turbulent flow, oxidative stress,
HDL-Associated Lysophospholipids and Endothelial Dysfunction
Endothelial dysfunction accompanies several pathological conditions preceding clinically manifest CHD such as diabetes mellitus, hypertension, or chronic renal failure and was postulated to be an early event in the development of atherosclerosis. The dysfunctional endothelium is impaired in its ability to regulate the vascular tone by secretion of vasodilatory substances, to serve as a barrier against atherogenic lipoproteins, and to reduce prothrombotic state. The decreased bioavailability of
HDL-Associated Lysophospholipids and Smooth Muscle Cells
The role of smooth muscle cells in the pathogenesis of atherosclerosis is controversially discussed. The development of atherosclerotic plaque is accompanied by the migration of smooth muscle cells from the media into the intima, where they contribute to inflammation by secreting cytokines and chemokines and MMPs and are ultimately transformed into foam cells. On the other hand, smooth muscle cells are believed to stabilize the fibrous cap and thereby to prevent atherosclerotic plaque rupture.
HDL-Associated Lysophospholipids and Transforming Growth Factor β
Transforming growth factor β (TGF-β) was initially recognized as a deactivating factor for macrophages, with the ability to suppress proinflammatory cytokine production (Mallat and Tedgui 2002). Recent studies revealed the critical role of TGF-β in the inhibition of the T-cell proliferation and the TH1 lineage commitment. Furthermore, TGF-β exerts anti-inflammatory effects on vascular cells by reducing the expression of adhesion molecules and chemokines and by preserving endothelial vasodilator
Conclusion and Future Perspectives
The vast body of evidence accumulated over the recent years suggests that intracellular signaling events arising in response to cell stimulation with HDL essentially contribute to the anti-inflammatory and thereby to the antiatherogenic effects exerted by this lipoprotein. We suggest that the HDL-associated lysosphingolipids account for a significant portion of HDL-induced signal transduction. Lysosphingolipids are amphipathic molecules, and their ability to freely diffuse between HDL and the
References (56)
- et al.
Lysophospholipid G protein-coupled receptors
J Biol Chem
(2004) - et al.
Antiproliferative properties of sphingosine 1-phosphate in human hepatic myofibroblasts. A cyclooxygenase-2 mediated pathway
J Biol Chem
(2000) - et al.
Distribution of glycosphingolipids in the serum lipoproteins of normal human subjects and patients with hypo- and hyperlipidemias
J Lipid Res
(1976) - et al.
Apolipoprotein A-I activates cellular cAMP signaling through the ABCA1 transporter
J Biol Chem
(2004) - et al.
Sphingosine 1-phosphate may be a major component of plasma lipoproteins responsible for the cytoprotective actions in human umbilical vein endothelial cells
J Biol Chem
(2001) - et al.
High density lipoprotein-induced endothelial nitric-oxide synthase activation is mediated by Akt and MAP kinases
J Biol Chem
(2003) - et al.
Suppression of endothelial cell apoptosis by high density lipoproteins (HDL) and HDL-associated lysosphingolipids
J Biol Chem
(2001) - et al.
HDL and arteriosclerosis: beyond reverse cholesterol transport
Atherosclerosis
(2002) - et al.
High density lipoprotein-associated lysosphingolipids reduce E-selectin expression in human endothelial cells
Biochem Biophys Res Commun
(2003) - et al.
EDG1 is a functional sphingosine-1-phosphate receptor that is linked via a Gi/o to multiple signaling pathways, including phospholipase C activation, Ca2+ mobilization, Ras-mitogen-activated protein kinase activation, and adenylate cyclase inhibition
J Biol Chem
(1998)
EDG3 is a functional receptor specific for sphingosine 1-phosphate and sphingosylphosphorylcholine with signaling characteristics distinct from EDG1 and AGR16
Biochem Biophys Res Commun
High-density lipoprotein increases the abundance of eNOS protein in human vascular endothelial cells by increasing its half-life
J Am Coll Cardiol
High-density lipoprotein inhibits migration of vascular smooth muscle cells through its sphingosine 1-phosphate component
Atherosclerosis
Janus kinase 2 modulates the apolipoprotein interactions with ABCA1 required for removing cellular cholesterol
J Biol Chem
Activation of a high affinity G protein-coupled plasma membrane receptor by sphingosine-1-phosphate
J Biol Chem
Sphingosine 1-phosphate cross-activates the Smad signaling cascade and mimics transforming growth factor-beta-induced cell responses
J Biol Chem
Edg-6 as a putative sphingosine 1-phosphate receptor coupling to Ca(2+) signaling pathway
Biochem Biophys Res Commun
Correlation of high density lipoprotein (HDL)-associated sphingosine 1-phosphate with serum levels of HDL-cholesterol and apolipoproteins
Atherosclerosis
The protective role of HDL
Restoration of endothelial function by increasing high-density lipoprotein in subjects with isolated low high-density lipoprotein
Circulation
Sphingosine-1-phosphate prevents tumor necrosis factor-{alpha}-mediated monocyte adhesion to aortic endothelium in mice
Arterioscler Thromb Vasc Biol
Regulation of plasma high-density lipoprotein levels by the ABCA1 transporter and the emerging role of high-density lipoprotein in the treatment of cardiovascular disease
Arterioscler Thromb Vasc Biol
High-density lipoproteins protect isolated rat hearts from ischemia–reperfusion injury by reducing cardiac tumor necrosis factor-alpha content and enhancing prostaglandin release
Circ Res
Autotoxin hydrolyzes sphingosylphosphorylcholine to produce the regulator of migration, sphingosine-1-phosphate
Cancer Res
Elevation of plasma high-density lipoprotein concentration reduces interleukin-1-induced expression of E-selectin in an in vivo model of acute inflammation
Circulation
High-density lipoproteins reduce the intestinal damage associated with ischemia/reperfusion and colitis
Shock
Systemic inflammatory parameters in patients with atherosclerosis of the coronary and peripheral arteries
Arterioscler Thromb Vasc Biol
Occurrence of sulfatide as a major glycosphingolipid in WHHL rabbit serum lipoproteins
J Biochem
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2018, American Journal of the Medical SciencesCitation Excerpt :HDL exerts a variety of antiatherogenic actions. Besides its reverse cholesterol transport promotive effect, it inhibits LDL oxidation, smooth muscle cell migration and platelet aggregation, and ameliorates endothelial dysfunction.3-7 However, HDL may not always be antiatherosclerotic.
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2016, Pharmacology and TherapeuticsCitation Excerpt :Such data reveal that the fluidity of HDL surface lipids is a key structural determinant of both the cholesterol efflux capacity and antioxidative activity of these lipoprotein particles. Minor HDL-associated sphingolipids, such as sphingosine-1-phosphate (S1P), sphingosylphosphorylcholine and lysosulfatide, may significantly contribute to HDL-mediated protection of cells from apoptosis and equally to enhancement of vasodilatation (Kimura et al., 2001; Okajima, 2002; Kimura et al., 2003; Nofer & Assmann, 2005; Zhang et al., 2005). Thus, S1P interacts with S1P receptors, activating intracellular signaling cascades which include the small G protein Ras-related C3 botulinum toxin substrate 1 (Rac), Src kinase, phosphoinositide 3-kinase (PI3K), protein kinase B Akt (Akt) and mitogen-activated protein kinase (MAPK), thereby enhancing nitric oxide (NO) production by endothelial cells (Spiegel & Milstien, 2003).
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2013, Journal of Lipid ResearchCitation Excerpt :Primary sources of plasma S1P are represented by erythrocytes and platelets (28, 29). Other biologically active lysosphingolipids carried by HDL include sphingosylphosphorylcholine (lysosphingomyelin; Table 1) and lysosulfatide (30). Other minor HDL sphingolipids are represented by glycosphingolipids, gangliosides, and sulfatides (31–35); lipidomic data on molecular species of these lipids are scarce.
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