title: Small, dense high-density lipoprotein 3 particles exhibit defective antioxidative and anti-inflammatory function in familial hypercholesterolemia: Partial correction by low-density lipoprotein apheresis.
abstract: BACKGROUND
  Familial hypercholesterolemia (FH) features elevated oxidative stress and accelerated atherosclerosis driven by elevated levels of atherogenic lipoproteins relative to subnormal levels of atheroprotective high-density lipoprotein (HDL). Small, dense HDL3 potently protects low-density lipoprotein (LDL) against proinflammatory oxidative damage.
  
  
  OBJECTIVE
  To determine whether antioxidative and/or anti-inflammatory activities of HDL are defective in FH and whether such defects are corrected by LDL apheresis.
  
  
  METHODS
  Antioxidative and antiinflammatory activities of HDL were evaluated as protection of reference LDL from oxidative stress and capacity to prevent accumulation of proinflammatory oxidised lipids, respectively. Lipid surface rigidity of HDL was assessed using a fluorescent probe. HDL components were measured by analytical approaches. Systemic oxidative stress was characterized as plasma 8-isoprostanes.
  
  
  RESULTS
  Pre-LDL-apheresis, FH patients (n = 10) exhibited elevated systemic oxidative stress (3.3-fold, P < 0.001) vs. sex- and age-matched normolipidemic controls (n = 10). Both antioxidative and antiinflammatory activity of HDL3 were impaired (up to -91%, P < 0.01) in FH. Sphingomyelin and saturated fatty acid contents were elevated in FH HDL3, resulting in enhanced lipid surface rigidity. The surface lipid content (phospholipids, free cholesterol) was reduced in FH (up to -15%, P < 0.001), whereas content of core lipids (cholesteryl esters, triglycerides) was elevated (up to +17%, P < 0.001). Molar apolipoprotein A-I content of HDL3 was subnormal in FH. A single LDL-apheresis session partially corrected (by up to 76%) deficient HDL antiatherogenic activities, attenuated systemic oxidative stress and partially normalised both the lipid composition and surface rigidity of HDL particles.
  
  
  CONCLUSIONS
  FH features elevated oxidative stress and deficient antioxidative and anti-inflammatory activities of small, dense HDL3; such functional deficiency is intimately linked to anomalies in lipid and protein composition, which may impair the capacity of HDL to acquire and inactivate oxidized lipids.
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Paris, France; AP-HP, Groupe hospitalier Pitié-Salpétrière, Paris, France; National Institute for Health and Medical Research (INSERM), Paris, France.
authors.forename: Hala
authors.initials: H
authors.lastname: Hussein
authors.affiliation: AP-HP, Groupe hospitalier Pitié-Salpétrière, Paris, France.
authors.forename: Samir
authors.initials: S
authors.lastname: Saheb
authors.affiliation: National Institute for Health and Medical Research (INSERM), Paris, France; Hôpital Bicetre, Bicetre, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Couturier
authors.affiliation: AP-HP, Groupe hospitalier Pitié-Salpétrière, Paris, France.
authors.forename: Marielle
authors.initials: M
authors.lastname: Atassi
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Paris, France; AP-HP, Groupe hospitalier Pitié-Salpétrière, Paris, France; National Institute for Health and Medical Research (INSERM), Paris, France.
authors.forename: Alexina
authors.initials: A
authors.lastname: Orsoni
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Paris, France; AP-HP, Groupe hospitalier Pitié-Salpétrière, Paris, France; National Institute for Health and Medical Research (INSERM), Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Carrié
authors.affiliation: Hôpital Bicetre, Bicetre, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Therond
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Paris, France; AP-HP, Groupe hospitalier Pitié-Salpétrière, Paris, France; National Institute for Health and Medical Research (INSERM), Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Chantepie
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Paris, France; AP-HP, Groupe hospitalier Pitié-Salpétrière, Paris, France; National Institute for Health and Medical Research (INSERM), Paris, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Robillard
authors.affiliation: AP-HP, Groupe hospitalier Pitié-Salpétrière, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Bruckert
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Paris, France; AP-HP, Groupe hospitalier Pitié-Salpétrière, Paris, France; National Institute for Health and Medical Research (INSERM), Paris, France.
authors.forename: M John
authors.initials: MJ
authors.lastname: Chapman
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Paris, France; AP-HP, Groupe hospitalier Pitié-Salpétrière, Paris, France; National Institute for Health and Medical Research (INSERM), Paris, France. Electronic address: anatol.kontush@upmc.fr.
authors.forename: Anatol
authors.initials: A
authors.lastname: Kontush
mesh_terms: D000328:Adult; D000975:Antioxidants / Q000737:chemistry* / Q000378:metabolism*; D001781:Blood Component Removal; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000628:therapy; D007249:Inflammation / Q000378:metabolism; D053440:Lipoproteins, HDL3 / Q000097:blood / Q000737:chemistry* / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000097:blood*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D010316:Particle Size
chemical_list: D000975:Antioxidants; D005609:Free Radicals; D053440:Lipoproteins, HDL3; D008077:Lipoproteins, LDL
keywords: Anti-inflammatory activity; Antioxidative activity; Apolipoprotein A-I; Familial hypercholesterolemia; LDL apheresis; Lipid surface rigidity; Small, dense HDL