title: Distinct patterns of transforming growth factor-beta isoform and receptor expression in human atherosclerotic lesions. Colocalization implicates TGF-beta in fibrofatty lesion development.
abstract: BACKGROUND
  Some animal studies suggest that transforming growth factor-beta (TGF-beta) protects vessels from atherosclerosis by preventing intima formation, but others indicate a role in vessel proteoglycan accumulation and lipoprotein retention. To distinguish between these possibilities in humans, immunohistochemical studies were performed examining the coexpression of TGF-beta isoforms and the TGF-beta receptors ALK-5 and TbetaR-II in aorta during the various stages of atherosclerotic lesion development.
  
  
  RESULTS
  The spatial relationships between TGF-beta1, TGF-beta3, ALK-5, and TbetaR-II expression were compared in aortic segments from 21 subjects. Nonatherosclerotic intima contained predominantly TGF-beta1, low concentrations of TbetaR-II, and barely detectable amounts of ALK-5. In contrast, fatty streaks/fibrofatty lesions contained high concentrations of both TGF-beta isoforms. Smooth muscle cells (SMCs), macrophages, and foam cells of macrophage and SMC origin contributed to these high levels. These lesions also contained high, colocalized concentrations of ALK-5 and TbetaR-II. Despite fibrous plaques containing TGF-beta1, its receptors were at detection limits. We found no evidence for truncated TbetaR-II expression in either normal intima or the various atherosclerotic lesions.
  
  
  CONCLUSIONS
  TGF-beta appears to be most active in lipid-rich aortic intimal lesions. The findings support the hypothesis that TGF-beta contributes primarily to the pathogenesis of lipid-rich atherosclerotic lesions by stimulating the production of lipoprotein-trapping proteoglycans, inhibiting smooth muscle proliferation, and activating proteolytic mechanisms in macrophages.
authors.affiliation: Baker Medical Research Institute and Alfred Hospital, Melbourne, Victoria, Australia. alex.bobik@baker.edu.au
authors.forename: A
authors.initials: A
authors.lastname: Bobik
authors.forename: A
authors.initials: A
authors.lastname: Agrotis
authors.forename: P
authors.initials: P
authors.lastname: Kanellakis
authors.forename: R
authors.initials: R
authors.lastname: Dilley
authors.forename: A
authors.initials: A
authors.lastname: Krushinsky
authors.forename: V
authors.initials: V
authors.lastname: Smirnov
authors.forename: E
authors.initials: E
authors.lastname: Tararak
authors.forename: M
authors.initials: M
authors.lastname: Condron
authors.forename: G
authors.initials: G
authors.lastname: Kostolias
mesh_terms: D030201:Activin Receptors, Type I; D000328:Adult; D000368:Aged; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D005355:Fibrosis; D006801:Humans; D007150:Immunohistochemistry; D007536:Isomerism; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D012016:Reference Values; D014018:Tissue Distribution / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625841:TGFBR1 protein, human