title: Elevated atherosclerosis-related gene expression, monocyte activation and microparticle-release are related to increased lipoprotein-associated oxidative stress in familial hypercholesterolemia.
abstract: OBJECTIVE
  Animal and in vitro studies have suggested that hypercholesterolemia and increased oxidative stress predisposes to monocyte activation and enhanced accumulation of oxidized LDL cholesterol (oxLDL-C) through a CD36-dependent mechanism. The aim of this study was to investigate the hypothesis that elevated oxLDL-C induce proinflammatory monocytes and increased release of monocyte-derived microparticles (MMPs), as well as up-regulation of CD36, chemokine receptors and proinflammatory factors through CD36-dependent pathways and that this is associated with accelerated atherosclerosis in subjects with heterozygous familial hypercholesterolemia (FH), in particular in the presence of Achilles tendon xanthomas (ATX).
  
  
  RESULTS
  We studied thirty FH subjects with and without ATX and twenty-three healthy control subjects. Intima-media thickness (IMT) and Achilles tendon (AT) thickness were measured by ultrasonography. Monocyte classification and MMP analysis were performed by flow cytometry. Monocyte expression of genes involved in atherosclerosis was determined by quantitative PCR. IMT and oxLDL-C were increased in FH subjects, especially in the presence of ATX. In addition, FH subjects had elevated proportions of intermediate CD14++CD16+ monocytes and higher circulating MMP levels. Stepwise linear regression identified oxLDL-C, gender and intermediate monocytes as predictors of MMPs. Monocyte expression of pro-atherogenic and pro-inflammatory genes regulated by oxLDL-C-CD36 interaction was increased in FH, especially in ATX+ subjects. Monocyte chemokine receptor CX3CR1 was identified as an independent contributor to IMT.
  
  
  CONCLUSIONS
  Our data support that lipoprotein-associated oxidative stress is involved in accelerated atherosclerosis in FH, particularly in the presence of ATX, by inducing pro-inflammatory monocytes and increased release of MMPs along with elevated monocyte expression of oxLDL-C-induced atherosclerosis-related genes.
authors: Danish PhD School of Molecular Metabolism, University of Southern Denmark, Odense, Denmark; Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark.
authors: Morten
authors: M
authors: Hjuler Nielsen
authors: Department of Medicine and Cardiology A, Aarhus University Hospital, Aarhus, Denmark.
authors: Helle
authors: H
authors: Irvine
authors: Department of Radiology, Aarhus University Hospital, Aarhus, Denmark.
authors: Simon
authors: S
authors: Vedel
authors: Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark.
authors: Bent
authors: B
authors: Raungaard
authors: Department of Endocrinology M, Odense University Hospital, Odense, Denmark.
authors: Henning
authors: H
authors: Beck-Nielsen
authors: Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark.
authors: Aase
authors: A
authors: Handberg
mesh_terms: D000328:Adult; D050197:Atherosclerosis / Q000150:complications* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018955:CD36 Antigens / Q000235:genetics / Q000276:immunology; D059168:Carotid Intima-Media Thickness; D055252:Cell-Derived Microparticles / Q000276:immunology / Q000473:pathology; D008078:Cholesterol, LDL / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008077:Lipoproteins, LDL / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology* / Q000473:pathology; D018384:Oxidative Stress; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology
chemical_list: D018955:CD36 Antigens; D008078:Cholesterol, LDL; D008077:Lipoproteins, LDL; D019707:Receptors, Chemokine; C099252:oxidized low density lipoprotein