Small dense HDLs display potent vasorelaxing activity, reflecting their elevated content of sphingosine-1-phosphate

Laurence Perségol,Maryam Darabi,Carolane Dauteuille,Marie Lhomme,Sandrine Chantepie,Kerry-Anne Rye,Patrice Therond,M John Chapman,Robert Salvayre,Anne Nègre-Salvayre,Philippe Lesnik,Serge Monier,Anatol Kontush

doi:10.1194/jlr.m076927

Abstract

The functional heterogeneity of HDL is attributed to its diverse bioactive components. We evaluated whether the vasodilatory effects of HDL differed across HDL subpopulations, reflecting their distinct molecular composition. The capacity of five major HDL subfractions to counteract the inhibitory effects of oxidized LDL on acetylcholine-induced vasodilation was tested in a rabbit aortic rings model. NO production, an essential pathway in endothelium-dependent vasorelaxation, was studied in simian vacuolating virus 40-transformed murine endothelial cells (SVECs). Small dense HDL3 subfractions displayed potent vasorelaxing activity (up to +31% vs. baseline, P < 0.05); in contrast, large light HDL2 did not induce aortic-ring relaxation when compared on a total protein basis. HDL3 particles were enriched with sphingosine-1-phosphate (S1P) (up to 3-fold vs. HDL2), with the highest content in HDL3b and -3c that concomitantly revealed the strongest vasorelaxing properties. NO generation was enhanced by HDL3c in SVECs (1.5-fold, P < 0.01), a phenomenon that was blocked by the S1P receptor antagonist, VPC 23019. S1P-enriched reconstituted HDL (rHDL) was a 1.8-fold (P < 0.01) more potent vasorelaxant than control rHDL in aortic rings. Small dense HDL3 particles displayed potent protective effects against oxidative stress-associated endothelium dysfunction, potentially reflecting their elevated content of S1P that might facilitate interaction with S1P receptors and ensuing NO generation.

Highlights

The functional heterogeneity of HDL is attributed to its diverse bioactive components
In order to evaluate this hypothesis, we examined five HDL subpopulations isolated from healthy normolipidemic subjects for their ability to counteract the inhibitory effects of oxidized LDL (oxLDL) on acetylcholine-induced vasodilation in isolated rab bit aortic rings
The content of major lipid classes showed a distinct trend to decrease in parallel with increment in HDL total protein and apoA-I [percentage by weight] from large light lipid-rich HDL2b to small dense protein-rich HDL3c, with only a minor degree of variation for most lipid classes relative to total lipid (Table 1)

Summary

Introduction

The functional heterogeneity of HDL is attributed to its diverse bioactive components. Small dense HDL3 particles displayed potent protective effects against oxidative stress-associated endothelium dysfunction, potentially reflecting their elevated content of S1P that might facilitate interaction with S1P receptors and ensuing NO generation.—Perségol, L., M. Small dense HDLs display potent vasorelaxing activity, reflecting their elevated content of sphingosine-1-phosphate. HDLs obtained from type 2 diabetic patients [7] or abdominally obese subjects [8] are incapable of counteracting the inhibitory effect of oxLDLs on vasorelaxation. Such HDL dys functionality was independent of HDL-cholesterol levels, as raising of HDL-cholesterol by glitazone did not restore.

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Conclusion