Defects of High-Density Lipoproteins in Coronary Artery Disease Caused by Low Sphingosine-1-Phosphate Content

Sattler, Katherine; Gräler, Markus H.; Keul, Petra; Weske, Sarah; Reimann, Christina-Maria; Jindrová, Helena; Kleinbongard, Petra; Sabbadini, Roger A.; Bröcker-Preuß, Martina; Erbel, Raimund; Heusch, Gerd; Levkau, Bodo

doi:10.1016/j.jacc.2015.07.057

Cited by 103 publications

(121 citation statements)

References 30 publications

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“…A highly significant inverse relationship exists between HDL-containing S1P levels and the occurrence of ischemic heart disease (179 ). S1P levels were also reduced in patients with acute MI and stable CAD, with preclinical rodent assays demonstrating that administering S1P in vivo can correct HDL dysfunction in CAD (180,181 ). These data suggest that S1P has an active involvement in CVD pathogenesis and that future assays quantifying S1P content of HDL could be useful as a cardiovascular risk biomarker.…”

Section: Composition and Role Of Hdl-associated Lipidsmentioning

confidence: 76%

The Changing Face of HDL and the Best Way to Measure It

Karathanasis¹,

Freeman

Gordon

et al. 2017

Clinical Chemistry

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BACKGROUND: HDL cholesterol (HDL-C) is a commonly used lipid biomarker for assessing cardiovascular health. While a central focus has been placed on the role of HDL in the reverse cholesterol transport (RCT) process, our appreciation for the other cardioprotective properties of HDL continues to expand with further investigation into the structure and function of HDL and its specific subfractions. The development of novel assays is empowering the research community to assess different aspects of HDL function, which at some point may evolve into new diagnostic tests. CONTENT:This review discusses our current understanding of the formation and maturation of HDL particles via RCT, as well as the newly recognized roles of HDL outside RCT. The antioxidative, antiinflammatory, antiapoptotic, antithrombotic, antiinfective, and vasoprotective effects of HDL are all discussed, as are the related methodologies for assessing these different aspects of HDL function. We elaborate on the importance of protein and lipid composition of HDL in health and disease and highlight potential new diagnostic assays based on these parameters.

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Section: Composition and Role Of Hdl-associated Lipidsmentioning

confidence: 76%

The Changing Face of HDL and the Best Way to Measure It

Karathanasis¹,

Freeman

Gordon

et al. 2017

Clinical Chemistry

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“…89 Moreover, a reduced HDL-associated S1P content has been related to defects in S1P-dependent activation of ERK1/2 and Akt signaling pathways as well as eNOS phosphorylation at Ser1177 in vascular endothelial cells in patients with CAD. 116 In vitro loading of both healthy and CAD HDL particles with additional S1P improved the effects of HDL on endothelial ERK1/2 and Akt activation, eNOSactivating phosphorylation, and vasorelaxation in pre-contracted arteries. 116 This loading may not only be an experimental model but may also happen in vivo, because HDL induces S1P efflux from erythrocytes and other cells by apoM dependent and -independent mechanisms.…”

Section: Sphingolipidsmentioning

confidence: 91%

“…116 In vitro loading of both healthy and CAD HDL particles with additional S1P improved the effects of HDL on endothelial ERK1/2 and Akt activation, eNOSactivating phosphorylation, and vasorelaxation in pre-contracted arteries. 116 This loading may not only be an experimental model but may also happen in vivo, because HDL induces S1P efflux from erythrocytes and other cells by apoM dependent and -independent mechanisms. 103 It may hence well be that HDL are locally uploaded with S1P by endothelial cells or circulating blood cells so that the ex vivo measured S1P levels in HDL underestimate the in vivo situation.…”

Section: Sphingolipidsmentioning

confidence: 91%

“…One study reported 4 to 5 times higher amounts of S1P in HDL of healthy control subjects compared to HDL particles of patients with stable CAD. 115,116 Another case-control study also found S1P concentrations lowered in HDL of patients with ACS or CAD compared to control HDL, but much less pronounced. 89 Moreover, the concentration of HDL-bound plasma S1P was inversely proportional to the severity of angina symptoms in CAD patients.…”

Section: Sphingolipidsmentioning

confidence: 97%

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Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Annema

Eckardstein

2016

Translational Research

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Low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risks of coronary heart disease. HDL mediates cholesterol efflux from macrophages for reverse transport to the liver and elicits many anti-inflammatory and anti-oxidative activities which are potentially antiatherogenic. Nevertheless, HDL has not been successfully targeted by drugs for prevention or treatment of cardiovascular diseases. One potential reason is the targeting of HDL cholesterol which does not capture the structural and functional complexity of HDL particles. Hundreds of lipid species and dozens of proteins as well as several microRNAs have been identified in HDL. This physiological heterogeneity is further increased in pathologic conditions due to additional quantitative and qualitative molecular changes of HDL components which have been associated with both loss of physiological function and gain of pathologic dysfunction. This structural and functional complexity of HDL has prevented clear assignments of molecules to the functions of normal HDL and dysfunctions of pathologic HDL. Systematic analyses of structure-function relationships of HDL-associated molecules and their modifications are needed to test the different components and functions of HDL for their relative contribution in the pathogenesis of atherosclerosis. The derived biomarkers and targets may eventually help to exploit HDL for treatment and diagnostics of cardiovascular diseases.

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“…It has been recently suggested that S1P bound to ApoM-containing HDL activates endothelial S1PR1 and results in a suppression of inflammatory responses (53). Although the structure of the ApoM protein supports the binding of S1P and HDL-associated S1P is bound specifically to ApoM such that ApoM-containing HDL contain S1P, whereas HDL devoid of ApoM do not (52), Sattler et al (54) have clearly demonstrated that S1P can be loaded in vitro or in vivo onto HDL, which are virtually absent of ApoM, and restore the defective signaling of the HDLs. We have shown previously that the S1P content of HDL can be increased significantly after in vitro incubation of the HDL particle with molecular S1P (16) and that this supplemented S1P is biologically active.…”

Section: Discussionmentioning

confidence: 99%

S1P in HDL promotes interaction between SR-BI and S1PR1 and activates S1PR1-mediated biological functions: calcium flux and S1PR1 internalization

Lee

Appleton

El‐Shewy

et al. 2017

Journal of Lipid Research

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Journal of Lipid Research Volume 58, 2017325 interaction between SR-BI and S1PR1 and activates S1PR1-mediated biological functions: calcium flux and S1PR1 internalization. J. Lipid Res. 2017. 58: 325-338.Supplementary key words high density lipoprotein • sphingosine 1-phosphate • protein-fragment complementation assay • scavenger receptor BI • S1P receptorsThe reverse transport of cholesterol from the periphery to the liver is often considered as the hallmark antiatherogenic function of HDL. SR-BI, the first molecularly characterized HDL receptor that plays a critical role in this metabolism, is abundantly expressed in several types of cells and tissue types, including the liver parenchyma, adrenal cortical cells, platelets, endothelial cells, smooth muscle cells, and macrophages. SR-BI facilitates the selective uptake of HDL cholesterol by cells, primarily in the form of cholesteryl esters. SR-BI also mediates the bidirectional flux of unesterified cholesterol and phospholipids between HDL and cells, which leads to an increase in cellular cholesterol mass and alters cholesterol distribution in plasma membrane domains (1-4).Numerous studies have detailed the various signaling pathways generated by the interaction of HDL with cell surface receptors that have been shown to induce myriad Abstract 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 HDLstimulated 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.-Lee,

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Defects of High-Density Lipoproteins in Coronary Artery Disease Caused by Low Sphingosine-1-Phosphate Content

Abstract: Reduced HDL-S1P content contributes to HDL dysfunction in CAD. It can be efficiently increased by S1P-loading in vitro and in vivo, providing a novel approach to correcting HDL dysfunction in CAD.

Cited by 103 publications

References 30 publications

The Changing Face of HDL and the Best Way to Measure It

The Changing Face of HDL and the Best Way to Measure It

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

S1P in HDL promotes interaction between SR-BI and S1PR1 and activates S1PR1-mediated biological functions: calcium flux and S1PR1 internalization

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