title: Regulation and splicing of scavenger receptor class B type I in human macrophages and atherosclerotic plaques.
abstract: BACKGROUND
  The protective role of high-density lipoprotein (HDL) in the cardiovascular system is related to its role in the reverse transport of cholesterol from the arterial wall to the liver for subsequent excretion via the bile. Scavenger receptor class B type I (SR-BI) binds HDL and mediates selective uptake of cholesterol ester and cellular efflux of cholesterol to HDL. The role of SR-BI in atherosclerosis has been well established in murine models but it remains unclear whether SR-BI plays an equally important role in atherosclerosis in humans. The aim of this study was to investigate the expression of SR-BI and its isoforms in human macrophages and atherosclerotic plaques.
  
  
  METHODS
  The effect of hypoxia and minimally modified low-density lipoprotein (mmLDL), two proatherogenic stimuli, on SR-BI expression was studied in human monocyte-derived macrophages from healthy subjects using real-time PCR. In addition, SR-BI expression was determined in macrophages obtained from subjects with atherosclerosis (n = 15) and healthy controls (n = 15). Expression of SR-BI isoforms was characterized in human atherosclerotic plaques and macrophages using RT-PCR and DNA sequencing.
  
  
  RESULTS
  SR-BI expression was decreased in macrophages after hypoxia (p < 0.005). In contrast, SR-BI expression was increased by exposure to mmLDL (p < 0.05). There was no difference in SR-BI expression in macrophages from patients with atherosclerosis compared to controls. In both groups, SR-BI expression was increased by exposure to mmLDL (p < 0.05). Transcripts corresponding to SR-BI and SR-BII were detected in macrophages. In addition, a third isoform, referred to as SR-BIII, was discovered. All three isoforms were also expressed in human atherosclerotic plaque. Compared to the other isoforms, the novel SR-BIII isoform was predicted to have a unique intracellular C-terminal domain containing 53 amino acids.
  
  
  CONCLUSIONS
  We conclude that SR-BI is regulated by proatherogenic stimuli in humans. However, we found no differences between subjects with atherosclerosis and healthy controls. This indicates that altered SR-BI expression is not a common cause of atherosclerosis. In addition, we identified SR-BIII as a novel isoform expressed in human macrophages and in human atherosclerotic plaques.
authors.affiliation: Research Centre for Endocrinology & Metabolism, Department of Internal Medicine, The Sahlgrenska Academy, Göteborg University, S-413 45 Göteborg, Sweden. Per-Arne.Svensson@medic.gu.se
authors.forename: Per-Arne
authors.initials: PA
authors.lastname: Svensson
authors.forename: Mikael C O
authors.initials: MC
authors.lastname: Englund
authors.forename: Magnus S C
authors.initials: MS
authors.lastname: Snäckestrand
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Hägg
authors.forename: Bertil G
authors.initials: BG
authors.lastname: Ohlsson
authors.forename: Veronika
authors.initials: V
authors.lastname: Stemme
authors.forename: Lillemor
authors.initials: L
authors.lastname: Mattsson-Hulten
authors.forename: Dag S
authors.initials: DS
authors.lastname: Thelle
authors.forename: Björn
authors.initials: B
authors.lastname: Fagerberg
authors.forename: Olov
authors.initials: O
authors.lastname: Wiklund
authors.forename: Lena M S
authors.initials: LM
authors.lastname: Carlsson
authors.forename: Björn
authors.initials: B
authors.lastname: Carlsson
mesh_terms: D000328:Adult; D017398:Alternative Splicing; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism; D001483:Base Sequence; D015687:Cell Hypoxia; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology; D051907:Lysosomal Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018909:src Homology Domains
chemical_list: D008077:Lipoproteins, LDL; D051907:Lysosomal Membrane Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D051116:Receptors, Scavenger; C495124:SCARB1 protein, human; C074299:SCARB2 protein, human; D051122:Scavenger Receptors, Class B; D012795:Sialoglycoproteins