title: High glucose promotes intracellular lipid accumulation in vascular smooth muscle cells by impairing cholesterol influx and efflux balance.
abstract: OBJECTIVE
  High glucose promotes macrophage-derived foam cell formation involved in increased influx or reduced efflux of lipids. The aim of this study is to investigate the influence of hyperglycaemia on foam cell transformation of vascular smooth muscle cells (VSMCs) and possible mechanisms contributing to these effects.
  
  
  RESULTS
  The results showed that high glucose increased the expression of CD36, a regulator of lipid influx, and suppressed the expression and activity of the adenosine triphosphate-binding cassette (ABC) transporter ABCG1, a regulator of cholesterol efflux to high-density lipoprotein, in a dose- and time-dependent manner. However, cholesterol efflux to lipid-free apoAI was not impaired. VSMCs exposed to high glucose readily developed into lipid-loaded cells, as demonstrated by Oil Red O staining and cholesterol content analysis. In addition, high glucose-induced down-regulation of ABCG1 was reversed by nuclear factor-kappaB (NF-kappaB) inhibitors BAY 11-7085 and tosyl-phenylalanine chloromethyl ketone and by the antioxidant N-acetyl-L-cysteine (NAC). This reversal was accompanied by reduced cellular lipid content. Also, NAC and NF-kappaB inhibitors can effectively block the high glucose-induced activity of NF-kappaB binding to DNA and/or peroxide production.
  
  
  CONCLUSIONS
  These results suggested that hyperglycaemia-induced foam cell formation in VSMCs was related to the imbalanced lipid flux by increasing CD36-mediated modified low-density lipoprotein uptake and reducing ABCG1-regulated cellular cholesterol efflux. Moreover, this effect was associated with increased oxidative stress and activated NF-kappaB pathway signalling.
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, Shaanxi 710061, People's Republic of China.
authors.forename: Jia-hong
authors.initials: JH
authors.lastname: Xue
authors.forename: Zuyi
authors.initials: Z
authors.lastname: Yuan
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Wei-ping
authors.initials: WP
authors.lastname: Zhang
authors.forename: Yu-ling
authors.initials: YL
authors.lastname: Tian
authors.forename: Wei-min
authors.initials: WM
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: Chiharu
authors.initials: C
authors.lastname: Kishimoto
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta / Q000166:cytology; D016632:Apolipoprotein A-I / Q000378:metabolism; D018955:CD36 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism; D005487:Foam Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism* / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010545:Peroxides / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013450:Sulfones / Q000494:pharmacology; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology
chemical_list: C419353:ABCG1 protein, human; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D000975:Antioxidants; D016632:Apolipoprotein A-I; C416282:BAY 11-7085; D018955:CD36 Antigens; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D016328:NF-kappa B; D009570:Nitriles; D010545:Peroxides; D013450:Sulfones; D014108:Tosylphenylalanyl Chloromethyl Ketone; D002784:Cholesterol; D005947:Glucose