REVIEW URRENT C OPINION
HDL quality or cholesterol cargo: what really matters – spotlight on sphingosine-1-phosphaterich HDL Emmanuel E. Egom a, Mamas A. Mamas b, and Handrean Soran b,c
Purpose of review The absolute level of HDL cholesterol (HDL-C) may not be the only criterion contributing to their antiatherothrombotic effects. This review focuses on evidence in support of the concept that HDL-bound sphingosine-1-phosphate (S1P) plays a role in different HDL atheroprotective properties and may represent a potential target for therapeutic interventions. Recent findings Recent large randomized clinical trials testing the hypothesis of raising HDL-C with niacin and dalcetrapib in statin-treated patients failed to improve cardiovascular outcomes. Emerging evidence suggests that many of the cardioprotective functions of HDL, such as vasodilation, angiogenesis and endothelial barrier function, protection against ischemia/reperfusion injury, and inhibition of atherosclerosis, may be attributable 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 some of HDL’s functions and atheroprotective properties. Keywords atherothrombotic, coronary artery disease, HDL, HDL functionality, sphingosine-1-phosphate
INTRODUCTION Plasma HDL is a heterogeneous collection of small discoid and spherical particles that are functionally diverse and differ in composition, size, and electrophoretic mobility [1–3]. HDL enzymes, phospholipids, proteins, and apolipoproteins have multiple biological effects that could contribute to HDL’s diverse properties like antiatherogenic, antiatherothrombotic, anti-inflammatory, antioxidant, antiglycation, and profibrinolytic activities [1,4,5 ,6]. Recent evidence suggests that the lysosphingolipid sphingosine-1-phosphate (S1P) may mediate many actions of HDL such as vasodilation, angiogenesis and endothelial barrier function, and protection against atherosclerosis and ischemia/reperfusion injury [7,8]. There is an inverse relationship between HDL-C concentration and cardiovascular disease (CVD) [9,10]. The Framingham Heart Study showed HDL-C to be an independent risk factor for CVD with 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 protect against CVD and there is accumulating evidence &
suggesting that simply increasing the circulating HDL-C does not necessarily confer cardiovascular benefits [13,14]. This leads to the hypothesis that the HDL in some patients may be dysfunctional and its other properties and compositions like S1P might be more important than its cholesterol cargo [1]. This review focuses on evidence in support of the concept that compositional differences of S1P in the HDL-containing fraction of human plasma may provide incremental information on cardiovascular risk
a
Department of Physiology and Biophysics, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada, bCardiovascular Research Group, School of Biomedicine, University of Manchester and cUniversity Department of Medicine, Central Manchester and Manchester Children’s University Hospitals Foundation Trust, Manchester, UK Correspondence to Dr Emmanuel E. Egom, Department of Physiology and Biophysics, Faculty of Medicine, Dalhousie University, Sir Charles Tupper Medical Building, Room 3F, 5850 College Street, Halifax, NS B3H 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
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Hyperlipidaemia and cardiovascular disease
KEY POINTS HDL-C is an independent risk factor for coronary heart disease and the most accepted mechanistic explanation is its role in reverse cholesterol transport. However, a variety of other atheroprotective functions of HDL have been described recently. There is an emerging role for HDL-associated S1P in HDL’s antiatherothrombotic properties. Evidence suggests that some of the atheroprotective functions of HDL, such as vasodilation, angiogenesis and endothelial barrier function, protection against ischemia/reperfusion injury, and inhibition of atherosclerosis, may be attributable to its S1P cargo. An inverse relationship between the level of HDL-S1P and CAD exists. HDL-S1P may represent a therapeutic target for future agents aimed at improving HDL composition and functionality.
and represent a potential target for therapeutic interventions.
EFFECT OF INCREASING PLASMA HDL ON CLINICAL OUTCOMES Multivariable analysis of the Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Cholesterol Intervention (VA-HIT) trial and the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies (ARBITER-6-HALTS) study and others implied that raising HDL-C should be the next target to ameliorate the progression of CVD [15–17]. However, increases in HDL-C may not result in the cardiovascular benefit that would be expected by extrapolation from prospective observational studies [18–20]. Despite the indirect evidence in support of benefit from raising HDL-C presented above, a 2009 meta-analysis of 108 randomized trials involving nearly 300 000 patients at risk for cardiovascular events of therapy (drugs or diet) failed to provide supportive evidence for such a benefit [18]. After adjustment for changes in LDL-C, there was no association of treatment-induced increases in HDL-C with risk ratios for coronary artery disease (CAD) deaths, CAD events, or total deaths. Two recent large randomized clinical trials testing the hypothesis of raising HDL-C with niacin and dalcetrapib in statin-treated patients failed to improve cardiovascular outcomes [21,22]. Additionally, the result of the Heart Protection Study 2-Treatment of 352
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HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) was announced in December 2012 with no benefit from combining tredaptive (combination of niacin and laropiprant) and simvastatin compared with simvastatin and placebo. Consistently, early Mendelian randomized analyses found that genetically increased HDL-C levels were not associated with a decreased cardiovascular risk [23,24]. The issue of whether higher levels of HDL-C caused by endothelial lipase gene polymorphism is associated with a lower risk of CAD events was directly addressed in another 2012 Mendelian randomization study. The authors reported that rise in HDL-C caused by this genetic polymorphism is not associated with a lower risk of CAD [25]. The mechanism by which HDL-C is increased may be critical in determining whether it reduces cardiovascular risk. The absence of premature CAD expected from such an extremely low HDL-C and apoAI in individuals with Tangier disease provides further support for the lack of association [26]. These findings raise the question whether HDL particles are functional in patients with high HDL-C. In one series of patients with elevated HDL-C levels who had CAD, it was found that the HDL particles were functionally impaired with regard to antioxidant and anti-inflammatory activities [27]. Recent evidence suggests that levels of S1P in the HDL-containing fraction of serum (HDL-S1P) are reduced in patients with stable CAD and acute myocardial infarction compared with controls [28].
SPHINGOSINE-1-PHOSPHATE, HDL, AND VASCULAR FUNCTION S1P is a signaling sphingolipid, which may regulate immune responses and inflammatory processes in a variety of different organ systems, including the cardiovascular system [29,30]. Apart from its cardiovascular effects, S1P pathway may have roles in signaling cascades controlling host responses to infection [31,32] in their human cytomegalovirus study showing that S1P may promote both the viral replication and the survival of the virus-infected cells. S1P signaling may also play a critical role in cancer progression including cell transformation/ oncogenesis, cell migration/metastasis, and tumor microenvironment neovascularization [16]. This complex interplay between S1P pathway and cancer is further supported by the finding that aberrant S1P signaling may reduce breast cancer survival and increase resistance to tamoxifen in patients with breast cancer [17]. The source of S1P in blood has only recently begun to be identified. Platelets, which possess highly active sphingosine kinase and lack the lyase Volume 24 Number 4 August 2013
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HDL and sphingosine-1-phosphate Egom et al.
that irreversibly degrades S1P, were originally proposed as the major source [29]. Indeed, activated platelets produce S1P [29]. However, transcription factor nuclear factor-E2-deficient mice, which virtually lack circulating platelets, have normal plasma S1P concentrations, suggesting that there must be other sources [29]. Recent data suggest that erythrocytes, which also lack S1P-degrading enzymes, appear to be a major contributor to plasma S1P [29]. Another proposed source is secretion of sphingosine kinase by vascular endothelial cells, which can act to phosphorylate circulating sphingosine [29]. S1P may, therefore, be synthesized by sphingosine kinase in the cells and exported to the extracellular space; however, the mechanism of S1P export remains unknown. ATP-binding cassette (ABC) transporters may be involved in the export of S1P. This is supported by the evidence that S1P release from platelets and erythrocytes is inhibited by glibenclamide, a nonspecific inhibitor of the ABC transporter [33]. How S1P is accumulated in plasma lipoprotein fractions still needs, however, to be clarified. Plasma S1P is mainly found in a lipoproteinbound form (60%), HDL being the major carrier (85%) [34,35]. The percentage of S1P transported in plasma lipoproteins may be positively correlated with HDL-C concentration suggesting that individuals with a high HDL-C level may have a high HDL-S1P level, which further supports the role of S1P as a mediator of HDL-induced antiatherogenic actions [36]. HDL particles appear to have multiple biological actions that may contribute to their antiatherothrombotic action including macrophage cholesterol efflux, maintenance of endothelial function, anti-inflammatory, antioxidant, and profibrinolytic activities [5 ,37]. Recent evidence suggests that S1P is a mediator of many of the above cardiovascular effects of HDL [7,8]. Interestingly, evidence suggests that the S1P analogue FTY720 may retard the development of atherosclerosis independently of plasma or HDL-C [38]. Recent evidence suggests that HDLassociated S1P may be responsible for the beneficial effects of these lipoproteins on vasodilatation, protection against postischemic inflammation, inhibition of oxidation, and synthesis of nitric oxide and prostacyclin (PGI2) [39–44]. Consistently, Nofer et al. [39] have shown that HDL-induced vasodilation is absent in S1P3-deficient mice . Furthermore, HDL activates S1P 2 and 3 receptors, which results in an increase of endothelial and vascular smooth muscle PGI2 synthesis through a mechanism depending on the upregulation at transcriptional level of the inducible COX isoform [45 ]. HDL may markedly inhibit platelet-derived growth &
&
factor-induced migration of vascular smooth muscle cells through S1P2 receptors [46]. Theilmeier et al. [40] have shown that HDL and S1P may attenuate the infarction size in an in-vivo mouse model of myocardial ischemia/reperfusion, through inhibition of the inflammatory neutrophil recruitment and the cardiomyocyte apoptosis in the infarcted area. The authors have also shown that the HDLinduced and S1P-induced actions are abolished by pharmacological nitric oxide synthesis inhibition, and are completely absent in S1P3-deficient mice [40]. S1P may also mediate HDL-induced cell survival through S1P1 pathways and migration through the S1P1 and S1P3 in human umbilical vein endothelial cells [47,48]. These observations may support the hypothesis that raising plasma level of HDLbound S1P may be associated with beneficial effects in CAD patients.
SPHINGOSINE-1-PHOSPHATE LEVELS IN THE HDL-CONTAINING FRACTION OF PLASMA OF PATIENTS WITH CORONARY ARTERY DISEASE Deutschman et al. [49] found that S1P was higher in patients with CAD and correlated with its severity. Sattler et al. [28] reported that plasma levels of HDLS1P are lower and those of non-HDL-bound S1P are higher in individuals with myocardial infarction and stable CAD compared with healthy controls. Moreover, the authors found both parameters to mirror the clinical severity of CAD symptoms [28]. The levels of non-HDL-bound plasma S1P increased significantly with increasing severity of symptoms compared with controls, whereas normalized HDLbound plasma S1P was inversely correlated with the severity of symptoms [28]. Furthermore, the authors showed that the amount of non-HDL-bound S1P is inversely associated with the S1P content of isolated HDL only in healthy individuals but not in patients with CAD, implying a functional alteration in the S1P exchange between HDL-S1P and non-HDLbound S1P plasma pools in CAD [28]. Argraves et al. [50] have found that levels of HDL-S1P are inversely related to the occurrence of CAD, but no significant correlation was observed between free S1P levels in total serum and the occurrence of CAD. Interestingly, this inverse relationship was independent of HDL-C levels [50]. The authors also found that in non-CAD individuals, the HDL-bound S1P is higher than that of CAD individuals suggesting that the mechanism regulating the partitioning of S1P to HDL versus other lipoproteins may act differently between CAD and non-CAD individuals. In a different experiment, the authors demonstrated that endothelial
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barrier response is influenced by the levels of HDLS1P supporting the concept that the atheroprotective effects of HDL may, at least in part, be associated with its S1P content, with higher levels being protective [50]. Consistently, Tong et al. [51 ] have recently demonstrated that patients with type 2 diabetes may have higher HDL-bound S1P, compared with HDL of healthy individuals, which may be the result of the body’s vasculoprotective mechanism of preventing or delaying complications from the disease, by inducing COX-2 expression and PGI-2 release . The distribution of plasma S1P between an HDL pool and a non-HDL pool may be important in the pathogenesis of CAD because of the different, even opposite effects S1P may exert on the cardiovascular system dependent on whether it is HDL-bound (HDL-S1P) or not [8]. In general, HDL-S1P has been shown to contribute to several beneficial effects of HDL [39–41]. In contrast, levels of free S1P have been shown to increase at inflammation sites, where it has been proposed to be involved in the propagation of inflammation [8,52]. These observations have led to the hypothesis that HDL may scavenge plasma S1P, thereby neutralizing its excess at inflammation sites [8,53]. At the same time, HDL could exert beneficial effects via its S1P cargo as summarized in Figure 1 [8]. &&
SUMMARY Many of the antiatherothrombotic effects of HDL may, at least in part, be attributable to its S1P cargo. An inverse relationship between the level of HDL-S1P and the presence and development of CAD exists. In addition, low levels of HDL-S1P are common in patients with CAD. This suggests a cardioprotective role of HDL-associated S1P but an increased risk with non-HDL-bound S1P. HDL-S1P may represent a future therapeutic target. Thus, therapies aimed at improving HDL composition or at compensating the CAD-associated defects in S1P uptake by HDL may hold promise for decreasing the risk for CAD. However, our understanding of the relationship between S1P-rich HDL and low HDL-S1P and, the mechanism of S1P integration with HDL needs further research.
CONCLUSION This review provides support for the concept that plasma HDL quality more than quantity and its cholesterol cargo provides incremental information on the cardiovascular risk and triggers the need for a new classification system of HDL that includes the information on the compositional differences of S1P in the human plasma HDL-containing fraction. In addition, this new classification is anticipated to be
HDL S1P
S1P
S1P
S1P
Antioxidant
S1P Antithrombotic
Anti-inflammatory
S1P
S1P
S1P
Antiapoptotic Enhanced reverse cholesterol efflux
Vasodilation and endothelial barrier function
Profibrinolytic
Protects against ischaemia/reperfusion injury
Angiogenesis
Antiatherothrombotic effect
FIGURE 1. Schematic overview of the multiple biological actions of HDL as a potential basis for antiatherothrombotic effects. Most of these HDL actions may be mediated by sphingosine-1-phosphate (S1P). 354
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of significant contribution in facilitating the identification and the stratification of patients with CAD. Acknowledgements The authors acknowledge support from Heart and Stroke Foundation of Canada Fellowship to E.E.E.; and Manchester Wellcome Trust Clinical Research Facility. Conflicts of interest There are no conflicts of interest.
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