Atheroprotective Effects of High-Density Lipoprotein-Associated Lysosphingolipids

doi:10.1016/j.tcm.2005.08.005

Trends in Cardiovascular Medicine

Volume 15, Issue 7, October 2005, Pages 265-271

https://doi.org/10.1016/j.tcm.2005.08.005 Get rights and content

Numerous epidemiological studies document an inverse relationship between plasma high-density lipoprotein (HDL) levels and the extent of atherosclerotic disease. The atheroprotective effects of HDL are more and more often seen in conjunction with the ability of HDL to restrict proinflammatory processes and thereby to carry out cytoprotection and organoprotection. Lysosphingolipids such as sphingosine 1 phosphate, sphingosylphosphorylcholine, and lysosulfatide are biologically active compounds that have recently been found to be associated with HDL particles. An increasing body of evidence suggests that several anti-inflammatory effects exerted by HDL can be attributed to the presence of lysosphingolipids in this lipoprotein fraction. In this review, we discuss the latest developments concerning the potential atheroprotective role of HDL-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 T_H1 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

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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.
Cigarette smoking disturbs plasma lipid level and lipoprotein metabolism; however, the effects of smoking on the functional state of high density lipoprotein (HDL) are still not clear. This study aimed to determine the antioxidant and antichemotactic properties of HDL and HDL-mediated cholesterol efflux in healthy subjects after cigarette smoking.
Healthy male subjects, including nonsmokers (n = 16) and chronic smokers (n = 8), were enrolled. After smoking 8 cigarettes within 2 hours, plasma HDL was isolated and tested. Copper-induced low density lipoprotein (LDL) oxidation was used to determine the antioxidant ability of HDL. The concentration of serum amyloid A was measured by Enzyme Linked Immunosorbent Assay. Chemotaxis was detected by transwell assay. HDL-mediated cholesterol efflux was measured using fluorescent cholesterol analog.
LDL baseline oxidation state was higher in chronic smokers than that in nonsmokers. Meanwhile, HDL-induced cholesterol efflux in macrophages in chronic smokers was significantly enhanced compared with that in nonsmokers. After acute smoking, both the antioxidant and antichemotactic ability of HDL declined in nonsmokers. However, in healthy chronic smokers, the effect of HDL on the susceptibility of LDL to oxidation was compensatorily enhanced. Nevertheless, their bodies were still in a higher oxidation state. Also, acute smoking did not affect HDL-mediated cholesterol efflux significantly in both nonsmokers and chronic smokers.
Our data suggest that acute smoking attenuates the antioxidant and antichemotactic abilities of HDL in nonsmokers. Chronic smokers are in a higher oxidative state, although the antioxidant function of their HDL is compensatorily enhanced.
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HDL normally transports about 50–70% of plasma sphingosine 1-phosphate (S1P), and the S1P in HDL reportedly mediates several HDL-associated biological effects and signaling pathways. The HDL receptor, SR-BI, as well as the cell surface receptors for S1P (S1PRs) may be involved partially and/or completely in these HDL-induced processes. Here we investigate the nature of the HDL-stimulated interaction between the HDL receptor, SR-BI, and S1PR1 using a protein-fragment complementation assay and confocal microscopy. In both primary rat aortic vascular smooth muscle cells and HEK293 cells, the S1P content in HDL particles increased intracellular calcium concentration, which was mediated by S1PR1. Mechanistic studies performed in HEK293 cells showed that incubation of cells with HDL led to an increase in the physical interaction between the SR-BI and S1PR1 receptors that mainly occurred on the plasma membrane. Model recombinant HDL (rHDL) particles formed in vitro with S1P incorporated into the particle initiated the internalization of S1PR1, whereas rHDL without supplemented S1P did not, suggesting that S1P transported in HDL can selectively activate S1PR1. In conclusion, these data suggest that S1P in HDL stimulates the transient interaction between SR-BI and S1PRs that can activate S1PRs and induce an elevation in intracellular calcium concentration.
Therapeutic applications of reconstituted HDL: When structure meets function
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Citation 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).
Reconstituted forms of HDL (rHDL) are under development for infusion as a therapeutic approach to attenuate atherosclerotic vascular disease and to reduce cardiovascular risk following acute coronary syndrome and ischemic stroke. Currently available rHDL formulations developed for clinical use contain apolipoprotein A-I (apoA-I) and one of the major lipid components of HDL, either phosphatidylcholine or sphingomyelin. Recent data have established that quantitatively minor molecular constituents of HDL particles can strongly influence their anti-atherogenic functionality. Novel rHDL formulations displaying enhanced biological activities, including cellular cholesterol efflux, may therefore offer promising prospects for the development of HDL-based, anti-atherosclerotic therapies. Indeed, recent structural and functional data identify phosphatidylserine as a bioactive component of HDL; the content of phosphatidylserine in HDL particles displays positive correlations with all metrics of their functionality. This review summarizes current knowledge of structure–function relationships in rHDL formulations, with a focus on phosphatidylserine and other negatively-charged phospholipids. Mechanisms potentially underlying the atheroprotective role of these lipids are discussed and their potential for the development of HDL-based therapies highlighted.
High-density lipoprotein subfractions: Current views and clinical practice applications
2014, Trends in Endocrinology and Metabolism
High-density lipoprotein (HDL) is astonishingly complex, but the de facto standard for its measurement has been remarkably simple: total cholesterol content. It is time to prioritize higher-resolution HDL measurement techniques that capture better the biologically and clinically important characteristics of HDL. Scientific advances have ushered in a new era in which we view HDL in terms of its subfractions, particle structure, metabolism, and functional integration of its proteome and lipidome. HDL subfractions appear to be associated with function. In general, smaller, denser HDL₃ is more tightly linked to favorable atheroprotective functions and clinical outcomes. Techniques to measure the cholesterol content or particle concentrations of HDL subfractions are available clinically. In the future, we anticipate subfractionating HDL based on its functional properties.
Thematic review series: High density lipoprotein structure, function, and metabolism: Unraveling the complexities of the HDL lipidome
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Citation 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.
Plasma high density lipoproteins (HDL) are small, dense, protein-rich particles compared with other lipoprotein classes; roughly half of total HDL mass is accounted for by lipid components. Phospholipids predominate in the HDL lipidome, accounting for 40–60% of total lipid, with lesser proportions of cholesteryl esters (30–40%), triglycerides (5–12%), and free cholesterol (5–10%). Lipidomic approaches have provided initial insights into the HDL lipidome with identification of over 200 individual molecular lipids species in normolipidemic HDL. Plasma HDL particles, however, reveal high levels of structural, compositional, and functional heterogeneity. Establishing direct relationships between HDL structure, composition, and atheroprotective functions bears the potential to identify clinically relevant HDL subpopulations. Furthermore, development of HDL-based therapies designed to target beneficial subspecies within the circulating HDL pool can be facilitated using this approach. HDL lipidomics can equally contribute to the identification of biomarkers of both normal and deficient HDL functionality, which may prove useful as biomarkers of cardiovascular risk. However, numerous technical issues remain to be addressed in order to make such developments possible. With all technical questions resolved, quantitative analysis of the molecular components of the HDL lipidome will contribute to expand our knowledge of cardiovascular and metabolic diseases.
High-density lipoproteins: A consensus statement from the National Lipid Association
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For >4 decades it has been recognized that elevated serum levels of high-density lipoprotein cholesterol (HDL-C) are associated with reduced risk of cardiovascular disease (CVD) and its sequelae. Many prospective observational studies performed around the world have confirmed an inverse relationship between HDL-C and cardiovascular risk in people irrespective of sex, race, or ethnicity. Consequently, it was assumed that, by extension, raising HDL-C through lifestyle modification and pharmacologic intervention would reduce risk of CVD. Animal studies are consistent with this assumption. Lipid treatment guidelines around the world promoted the recognition of HDL-C as a therapeutic target, especially in high-risk patients. Some post hoc analyses from randomized controlled trials also suggest that raising HDL-C beneficially affects the risk of CVD. However, a number of recent randomized studies putatively designed to test the “HDL hypothesis” have failed to show benefit. The results of these trials have caused many clinicians to question whether HDL-C is a legitimate therapeutic target. In response to the many questions and uncertainties raised by the results of these trials, the National Lipid Association convened an expert panel to evaluate the current status of HDL-C as a therapeutic target; to review the current state of knowledge of HDL particle structure, composition, and function; and to identify the salient questions yet to be answered about the role of HDL in either preventing or contributing to atherosclerotic disease. The expert panel's conclusions and clinical recommendations are summarized herein. The panel concludes that, although low HDL-C identifies patients at elevated risk, and much investigation suggests that HDL may play a variety of antiatherogenic roles, HDL-C is not a therapeutic target at the present time. Risk stratified atherogenic lipoprotein burden (low-density lipoprotein cholesterol and non–HDL-C) should remain the primary and secondary targets of therapy in patients at risk, as described by established guidelines. The National Lipid Association emphasizes that rigorous research into the biology and clinical significance of low HDL-C should continue. The development of novel drugs designed to modulate the serum levels and functionality of HDL particles should also continue. On the basis of an enormous amount of basic scientific and clinical investigation, a considerable number of reasons support the need to continue to investigate the therapeutic effect of modulating HDL structure and function.

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Atheroprotective Effects of High-Density Lipoprotein-Associated Lysosphingolipids

Section snippets

Discovery of Lysosphingolipids Associated With HDL

Lysosphingolipids in Plasma and Lipoproteins

HDL-Associated Lysophospholipids and Endothelial Reparatory Processes

HDL-Associated Lysophospholipids and Endothelial Dysfunction

HDL-Associated Lysophospholipids and Smooth Muscle Cells

HDL-Associated Lysophospholipids and Transforming Growth Factor β

Conclusion and Future Perspectives

J Biol Chem

J Biol Chem

J Lipid Res

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Atherosclerosis

Biochem Biophys Res Commun

J Biol Chem

Biochem Biophys Res Commun

J Am Coll Cardiol

Atherosclerosis

J Biol Chem

J Biol Chem

J Biol Chem

Biochem Biophys Res Commun

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