title: Age-dependent alteration of intraocular soluble heparan sulfate levels and its implications for proliferative diabetic retinopathy.
abstract: OBJECTIVE
  To assess the relationship between intraocular soluble heparan sulfate (HS) concentration and age in subjects with and without diabetic retinopathy.
  
  
  METHODS
  Vitreous from subjects with idiopathic maculopathies (n=17), i.e., macula hole or epiretinal membrane, or nonproliferative diabetic retinopathy (non-PDR; n=5) and aqueous humor from subjects with PDR (n=16), non-PDR (n=7), or cataracts (n=15) was collected. The levels of HS and vascular endothelial growth factor (VEGF) were measured using enzyme-linked immunosorbent assay. Concentrations of sulfated glycosaminoglycan were determined through dimethylmethylene blue-based assay. The effect of the vitreal HS level on the binding of exogenous VEGF to surface-bound heparin was determined in vitro.
  
  
  RESULTS
  The level of HS in vitreous samples from subjects with idiopathic maculopathies increased concomitantly with age (p=0.020, R²=0.327). Meanwhile, HS levels in aqueous humor were lower in PDR subjects than in non-PDR (p=0.003) and cataract subjects (p=0.007). However, the PDR subjects were significantly younger than the non-PDR subjects (p<0.001) or cataract subjects (p<0.001). When the three groups were controlled for age, the levels of HS glycosaminoglycans were no longer different between the three (p=0.247). The increasing level of HS or sulfated glycosaminoglycan in the vitreous was associated with its increased inhibitory effect on interaction between VEGF and surface heparin in vitro (p=0.014, R²=0.377).
  
  
  CONCLUSIONS
  The HS level of the intraocular fluid increased with age. The possible link between low HS in intraocular fluid and increased localization of VEGF at the retinal surface may provide one explanation for the higher susceptibility of younger subjects with diabetes mellitus to developing PDR.
authors.affiliation: Department of Ophthalmology, Nagoya University School of Medicine, Showa-ku, Nagoya, Japan. knishiguchi@ucl.ac.uk
authors.forename: Koji M
authors.initials: KM
authors.lastname: Nishiguchi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ushida
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tomida
authors.forename: Shu
authors.initials: S
authors.lastname: Kachi
authors.forename: Mineo
authors.initials: M
authors.lastname: Kondo
authors.forename: Hiroko
authors.initials: H
authors.lastname: Terasaki
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D001082:Aqueous Humor / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000378:metabolism* / Q000473:pathology; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D011485:Protein Binding; D012995:Solubility; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014822:Vitreous Body / Q000378:metabolism*; D055815:Young Adult
chemical_list: D006497:Heparan Sulfate; D042461:Vascular Endothelial Growth Factor A