title: Metabolic syndrome features small, apolipoprotein A-I-poor, triglyceride-rich HDL3 particles with defective anti-apoptotic activity.
abstract: The metabolic syndrome (MetS) phenotype is typically characterized by visceral obesity, insulin resistance, atherogenic dyslipidemia involving hypertriglyceridemia and subnormal levels of high density lipoprotein-cholesterol (HDL-C), oxidative stress and elevated cardiovascular risk. The potent antioxidative activity of small HDL3 is defective in MetS [Hansel B, et al. J Clin Endocrinol Metab 2004;89:4963-71]. We evaluated the functional capacity of small HDL3 particles from MetS subjects to protect endothelial cells from apoptosis induced by mildly oxidized low-density lipoprotein (oxLDL). MetS subjects presented an insulin-resistant obese phenotype, with hypertriglyceridemia, elevated apolipoprotein B and insulin levels, but subnormal HDL-C concentrations and chronic low grade inflammation (threefold elevation of C-reactive protein). When human microvascular endothelial cells (HMEC-1) were incubated with oxLDL (200 microg apolipoprotein B/ml) in the presence or absence of control HDL subfractions (25 microg protein/ml), small, dense HDL3b and 3c significantly inhibited cellular annexin V binding and intracellular generation of reactive oxygen species. The potent anti-apoptotic activity of small HDL3c particles was reduced (-35%; p<0.05) in MetS subjects (n=16) relative to normolipidemic controls (n=7). The attenuated anti-apoptotic activity of HDL3c correlated with abdominal obesity, atherogenic dyslipidemia and systemic oxidative stress (p<0.05), and was intimately associated with altered physicochemical properties of apolipoprotein A-I (apoA-I)-poor HDL3c, involving core cholesteryl ester depletion and triglyceride enrichment. We conclude that in MetS, apoA-I-poor, small, dense HDL3c exert defective protection of endothelial cells from oxLDL-induced apoptosis, potentially reflecting functional anomalies intimately associated with abnormal neutral lipid core content.
authors.affiliation: Université Pierre et Marie Curie-Paris 6, Paris F-75013, France.
authors.forename: Juliana A
authors.initials: JA
authors.lastname: de Souza
authors.forename: Cecile
authors.initials: C
authors.lastname: Vindis
authors.forename: Boris
authors.initials: B
authors.lastname: Hansel
authors.forename: Anne
authors.initials: A
authors.lastname: Nègre-Salvayre
authors.forename: Patrice
authors.initials: P
authors.lastname: Therond
authors.forename: Carlos V
authors.initials: CV
authors.lastname: Serrano
authors.forename: Sandrine
authors.initials: S
authors.lastname: Chantepie
authors.forename: Robert
authors.initials: R
authors.lastname: Salvayre
authors.forename: Eric
authors.initials: E
authors.lastname: Bruckert
authors.forename: M John
authors.initials: MJ
authors.lastname: Chapman
authors.forename: Anatol
authors.initials: A
authors.lastname: Kontush
mesh_terms: D016632:Apolipoprotein A-I / Q000097:blood* / Q000737:chemistry; D017209:Apoptosis / Q000502:physiology*; D008076:Cholesterol, HDL / Q000097:blood* / Q000737:chemistry; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007333:Insulin Resistance; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D010316:Particle Size; D017382:Reactive Oxygen Species / Q000378:metabolism; D014280:Triglycerides / Q000097:blood*
chemical_list: D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; D014280:Triglycerides; C099252:oxidized low density lipoprotein