hdl quality or cholesterol cargo

REVIEW

CURRENTOPINION HDL quality or cholesterol cargo: what really

matters – spotlight on sphingosine-1-phosphate-rich HDL

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a b b,c
Emmanuel E. Egom , Mamas A. Mamas , and Handrean Soran
Purpose of review

The absolute level of HDL cholesterol (HDL-C) may not be the only criterion contributing to theirantiatherothrombotic effects. This review focuses on evidence in support of the concept that HDL-boundsphingosine-1-phosphate (S1P) plays a role in different HDL atheroprotective properties and may representa potential target for therapeutic interventions.

Recent findings

Recent large randomized clinical trials testing the hypothesis of raising HDL-C with niacin and dalcetrapibin statin-treated patients failed to improve cardiovascular outcomes. Emerging evidence suggests that manyof the cardioprotective functions of HDL, such as vasodilation, angiogenesis and endothelial barrierfunction, protection against ischemia/reperfusion injury, and inhibition of atherosclerosis, may beattributable to its S1P cargo. HDL-associated S1P may represent a future therapeutic target.

Summary

HDL functionality is affected by its composition and there is evidence to suggest S1P plays a role in someof HDL’s functions and atheroprotective properties.

Keywords

atherothrombotic, coronary artery disease, HDL, HDL functionality, sphingosine-1-phosphate

aDepartment of Physiology and Biophysics, Faculty of Medicine, Dalhou-sie University, Halifax, Nova Scotia, Canada, bCardiovascular ResearchGroup, School of Biomedicine, University of Manchester and cUniversityDepartment of Medicine, Central Manchester andManchester Children’sUniversity Hospitals Foundation Trust, Manchester, UK

Correspondence to Dr Emmanuel E. Egom, Department of Physiologyand Biophysics, Faculty of Medicine, Dalhousie University, Sir CharlesTupper Medical Building, Room 3F, 5850 College Street, Halifax, NSB3H 4R2, Canada. Tel: +1 902 494 2268; fax: +1 902 494 1685;e-mail: [email protected]

Curr Opin Lipidol 2013, 24:351–356

DOI:10.1097/MOL.0b013e328361f822

INTRODUCTION

Plasma HDL is a heterogeneous collection of smalldiscoid and spherical particles that are functionallydiverse and differ in composition, size, and electro-phoretic mobility [1–3]. HDL enzymes, phospholi-pids, proteins, and apolipoproteins have multiplebiological effects that could contribute to HDL’sdiverse properties like antiatherogenic, antiathero-thrombotic, anti-inflammatory, antioxidant, anti-glycation, and profibrinolytic activities [1,4,5

&

,6].Recent evidence suggests that the lysosphingolipidsphingosine-1-phosphate (S1P) may mediate manyactions of HDL such as vasodilation, angiogenesisand endothelial barrier function, and protectionagainst atherosclerosis and ischemia/reperfusioninjury [7,8]. There is an inverse relationship betweenHDL-C concentration and cardiovascular disease(CVD) [9,10]. The Framingham Heart Study showedHDL-C to be an independent risk factor for CVDwith an increase in HDL-C of 1 mg/dl (0.026 mmol/l)associated with a risk reduction of 2–3% [11,12].However, high HDL levels do not always protectagainst CVD and there is accumulating evidence

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suggesting that simply increasing the circulatingHDL-C does not necessarily confer cardiovascularbenefits [13,14]. This leads to the hypothesis thatthe HDL in some patients may be dysfunctionaland its other properties and compositions like S1Pmight be more important than its cholesterol cargo[1]. This review focuses on evidence in support of theconcept that compositional differences of S1P in theHDL-containing fraction of human plasma may pro-vide incremental information on cardiovascular risk

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KEY POINTS

� HDL-C is an independent risk factor for coronary heartdisease and the most accepted mechanistic explanationis its role in reverse cholesterol transport. However, avariety of other atheroprotective functions of HDL havebeen described recently.

� There is an emerging role for HDL-associated S1P inHDL’s antiatherothrombotic properties.

� Evidence suggests that some of the atheroprotectivefunctions of HDL, such as vasodilation, angiogenesisand endothelial barrier function, protection againstischemia/reperfusion injury, and inhibition ofatherosclerosis, may be attributable to its S1P cargo.

� An inverse relationship between the level of HDL-S1Pand CAD exists.

� HDL-S1P may represent a therapeutic target for futureagents aimed at improving HDL compositionand functionality.

Hyperlipidaemia and cardiovascular disease

and represent a potential target for therapeutic inter-ventions.

EFFECT OF INCREASING PLASMA HDL ONCLINICAL OUTCOMES

Multivariable analysis of the Veterans AffairsCooperative Studies Program High-Density Lipopro-tein Cholesterol Intervention (VA-HIT) trial and theArterial Biology for the Investigation of the Treat-ment Effects of Reducing Cholesterol 6-HDL andLDL Treatment Strategies (ARBITER-6-HALTS) studyand others implied that raising HDL-C should be thenext target to ameliorate the progression of CVD[15–17]. However, increases in HDL-C may notresult in the cardiovascular benefit that would beexpected by extrapolation from prospective obser-vational studies [18–20].

Despite the indirect evidence in support ofbenefit from raising HDL-C presented above, a2009 meta-analysis of 108 randomized trials involv-ing nearly 300 000 patients at risk for cardiovascularevents of therapy (drugs or diet) failed to providesupportive evidence for such a benefit [18]. Afteradjustment for changes in LDL-C, there was noassociation of treatment-induced increases inHDL-C with risk ratios for coronary artery disease(CAD) deaths, CAD events, or total deaths. Tworecent large randomized clinical trials testing thehypothesis of raising HDL-C with niacin and dalce-trapib in statin-treated patients failed to improvecardiovascular outcomes [21,22]. Additionally, theresult of the Heart Protection Study 2-Treatment of

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HDL to Reduce the Incidence of Vascular Events(HPS2-THRIVE) was announced in December 2012with no benefit from combining tredaptive (combi-nation of niacin and laropiprant) and simvastatincompared with simvastatin and placebo. Consist-ently, early Mendelian randomized analyses foundthat genetically increased HDL-C levels were notassociated with a decreased cardiovascular risk[23,24]. The issue of whether higher levels ofHDL-C caused by endothelial lipase gene polymor-phism is associated with a lower risk of CAD eventswas directly addressed in another 2012 Mendelianrandomization study. The authors reported that risein HDL-C caused by this genetic polymorphism isnot associated with a lower risk of CAD [25]. Themechanism by which HDL-C is increased may becritical in determining whether it reduces cardio-vascular risk. The absence of premature CADexpected from such an extremely low HDL-C andapoAI in individuals with Tangier disease providesfurther support for the lack of association [26].

These findings raise the question whetherHDL particles are functional in patients with highHDL-C. In one series of patients with elevated HDL-Clevels who had CAD, it was found that the HDLparticles were functionally impaired with regard toantioxidant and anti-inflammatory activities [27].Recent evidence suggests that levels of S1P in theHDL-containing fraction of serum (HDL-S1P) arereduced in patients with stable CAD and acute myo-cardial infarction compared with controls [28].

SPHINGOSINE-1-PHOSPHATE, HDL, ANDVASCULAR FUNCTION

S1P is a signaling sphingolipid, which may regulateimmune responses and inflammatory processes in avariety of different organ systems, including thecardiovascular system [29,30]. Apart from its cardio-vascular effects, S1P pathway may have roles insignaling cascades controlling host responses toinfection [31,32] in their human cytomegalovirusstudy showing that S1P may promote both the viralreplication and the survival of the virus-infectedcells. S1P signaling may also play a critical role incancer progression including cell transformation/oncogenesis, cell migration/metastasis, and tumormicroenvironment neovascularization [16]. Thiscomplex interplay between S1P pathway and canceris further supported by the finding that aberrant S1Psignaling may reduce breast cancer survival andincrease resistance to tamoxifen in patients withbreast cancer [17].

The source of S1P in blood has only recentlybegun to be identified. Platelets, which possesshighly active sphingosine kinase and lack the lyase

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HDL and sphingosine-1-phosphate Egom et al.

that irreversibly degrades S1P, were originally pro-posed as the major source [29]. Indeed, activatedplatelets produce S1P [29]. However, transcriptionfactor nuclear factor-E2-deficient mice, which vir-tually lack circulating platelets, have normal plasmaS1P concentrations, suggesting that there must beother sources [29]. Recent data suggest that eryth-rocytes, which also lack S1P-degrading enzymes,appear to be a major contributor to plasma S1P[29]. Another proposed source is secretion of sphin-gosine kinase by vascular endothelial cells, whichcan act to phosphorylate circulating sphingosine[29]. S1P may, therefore, be synthesized bysphingosine kinase in the cells and exported tothe extracellular space; however, the mechanismof S1P export remains unknown. ATP-bindingcassette (ABC) transporters may be involved in theexport of S1P. This is supported by the evidencethat S1P release from platelets and erythrocytes isinhibited by glibenclamide, a nonspecific inhibitorof the ABC transporter [33]. How S1P is accumulatedin plasma lipoprotein fractions still needs, however,to be clarified.

Plasma S1P is mainly found in a lipoprotein-bound form (60%), HDL being the major carrier(85%) [34,35]. The percentage of S1P transportedin plasma lipoproteins may be positively correlatedwith HDL-C concentration suggesting that indi-viduals with a high HDL-C level may have a highHDL-S1P level, which further supports the role ofS1P as a mediator of HDL-induced antiatherogenicactions [36].

HDL particles appear to have multiple biologicalactions that may contribute to their antiathero-thrombotic action including macrophage choles-terol efflux, maintenance of endothelial function,anti-inflammatory, antioxidant, and profibrinolyticactivities [5

&

,37]. Recent evidence suggests that S1Pis a mediator of many of the above cardiovasculareffects of HDL [7,8]. Interestingly, evidence suggeststhat the S1P analogue FTY720 may retard the devel-opment of atherosclerosis independently of plasmaor HDL-C [38]. Recent evidence suggests that HDL-associated S1P may be responsible for the beneficialeffects of these lipoproteins on vasodilatation, pro-tection against postischemic inflammation, inhi-bition of oxidation, and synthesis of nitric oxideand prostacyclin (PGI2) [39–44]. Consistently,Nofer et al. [39] have shown that HDL-induced vaso-dilation is absent in S1P3-deficient mice . Further-more, HDL activates S1P 2 and 3 receptors, whichresults in an increase of endothelial and vascularsmooth muscle PGI2 synthesis through a mechan-ism depending on the upregulation at transcrip-tional level of the inducible COX isoform [45

&

].HDL may markedly inhibit platelet-derived growth

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factor-induced migration of vascular smooth musclecells through S1P2 receptors [46]. Theilmeier et al.[40] have shown that HDL and S1P may attenuatethe infarction size in an in-vivo mouse model ofmyocardial ischemia/reperfusion, through inhi-bition of the inflammatory neutrophil recruitmentand the cardiomyocyte apoptosis in the infarctedarea. The authors have also shown that the HDL-induced and S1P-induced actions are abolished bypharmacological nitric oxide synthesis inhibition,and are completely absent in S1P3-deficient mice[40]. S1P may also mediate HDL-induced cell sur-vival through S1P1 pathways and migration throughthe S1P1 and S1P3 in human umbilical vein endo-thelial cells [47,48]. These observations may supportthe hypothesis that raising plasma level of HDL-bound S1P may be associated with beneficial effectsin CAD patients.

SPHINGOSINE-1-PHOSPHATE LEVELS INTHE HDL-CONTAINING FRACTION OFPLASMA OF PATIENTS WITH CORONARYARTERY DISEASE

Deutschman et al. [49] found that S1P was higher inpatients with CAD and correlated with its severity.Sattler et al. [28] reported that plasma levels of HDL-S1P are lower and those of non-HDL-bound S1P arehigher in individuals with myocardial infarctionand stable CAD compared with healthy controls.Moreover, the authors found both parameters tomirror the clinical severity of CAD symptoms [28].The levels of non-HDL-bound plasma S1P increasedsignificantly with increasing severity of symptomscompared with controls, whereas normalized HDL-bound plasma S1P was inversely correlated with theseverity of symptoms [28]. Furthermore, the authorsshowed that the amount of non-HDL-bound S1P isinversely associated with the S1P content of isolatedHDL only in healthy individuals but not in patientswith CAD, implying a functional alteration in theS1P exchange between HDL-S1P and non-HDL-bound S1P plasma pools in CAD [28].

Argraves et al. [50] have found that levels ofHDL-S1P are inversely related to the occurrence ofCAD, but no significant correlation was observedbetween free S1P levels in total serum and theoccurrence of CAD. Interestingly, this inverserelationship was independent of HDL-C levels[50]. The authors also found that in non-CAD indi-viduals, the HDL-bound S1P is higher than that ofCAD individuals suggesting that the mechanismregulating the partitioning of S1P to HDL versusother lipoproteins may act differently betweenCAD and non-CAD individuals. In a different experi-ment, the authors demonstrated that endothelial


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barrier response is influenced by the levels of HDL-S1P supporting the concept that the atheroprotec-tive effects of HDL may, at least in part, be associatedwith its S1P content, with higher levels being pro-tective [50]. Consistently, Tong et al. [51

&&

] haverecently demonstrated that patients with type 2diabetes may have higher HDL-bound S1P, com-pared with HDL of healthy individuals, whichmay be the result of the body’s vasculoprotectivemechanism of preventing or delaying complicationsfrom the disease, by inducing COX-2 expression andPGI-2 release .

The distribution of plasma S1P between an HDLpool and a non-HDL pool may be important in thepathogenesis of CAD because of the different, evenopposite effects S1P may exert on the cardiovascularsystem dependent on whether it is HDL-bound(HDL-S1P) or not [8]. In general, HDL-S1P has beenshown to contribute to several beneficial effects ofHDL [39–41]. In contrast, levels of free S1P havebeen shown to increase at inflammation sites, whereit has been proposed to be involved in the propa-gation of inflammation [8,52]. These observationshave led to the hypothesis that HDL may scavengeplasma S1P, thereby neutralizing its excess atinflammation sites [8,53]. At the same time, HDLcould exert beneficial effects via its S1P cargo assummarized in Figure 1 [8].


S1P

Antioxidant

Enhanced rcholestero

Vasodilation andendothelial barrier

function

Antiatherotheffec

Antithrombotic

Antiapoptotic

HDL

S1P

S1P

S1P

FIGURE 1. Schematic overview of the multiple biological actionMost of these HDL actions may be mediated by sphingosine-1-pho


SUMMARY

Many of the antiatherothrombotic effects of HDLmay, at least in part, be attributable to its S1P cargo.An inverse relationship between the level of HDL-S1Pand the presence and development of CAD exists. Inaddition, low levels of HDL-S1P are common inpatients with CAD. This suggests a cardioprotectiverole of HDL-associated S1P but an increased risk withnon-HDL-bound S1P. HDL-S1P may represent afuture therapeutic target. Thus, therapies aimedat improving HDL composition or at compensatingthe CAD-associated defects in S1P uptake by HDLmay hold promise for decreasing the risk for CAD.However, our understanding of the relationshipbetween S1P-rich HDL and low HDL-S1P and, themechanism of S1P integration with HDL needsfurther research.

CONCLUSION

This review provides support for the concept thatplasma HDL quality more than quantity and itscholesterol cargo provides incremental informationon the cardiovascular risk and triggers the need for anew classification system of HDL that includes theinformation on the compositional differences of S1Pin the human plasma HDL-containing fraction. Inaddition, this new classification is anticipated to be


Anti-inflammatory

Profibrinolytic

Protects againstischaemia/reperfusion

injury

Angiogenesis

eversel efflux

rombotict

S1P

S1P

S1P

S1P

s of HDL as a potential basis for antiatherothrombotic effects.sphate (S1P).


HDL and sphingosine-1-phosphate Egom et al.

of significant contribution in facilitating the iden-tification and the stratification of patients withCAD.

Acknowledgements

The authors acknowledge support from Heart and StrokeFoundation of Canada Fellowship to E.E.E.; and Man-chester Wellcome Trust Clinical Research Facility.

Conflicts of interest

There are no conflicts of interest.

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51.&&

Tong X, Peng H, Liu D, et al. High-density lipoprotein of patients withtype 2 diabetes mellitus upregulates cyclooxgenase-2 expressionand prostacyclin I-2 release in endothelial cells: relationship with HDL-associated sphingosine-1-phosphate. Cardiovasc Diabetol 2013; 12:27.

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plasma components, including lipoproteins, regulates the lipid receptor-mediated actions. Biochem J 2000; 352:809–815.



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