title: Increased expression of heparanase in symptomatic carotid atherosclerosis.
abstract: OBJECTIVE
  Proliferation of smooth muscle cells (SMCs) can stabilize atherosclerotic lesions but the molecular mechanisms that regulate this process in humans are largely unknown. We have previously shown that heparan sulfate proteoglycans (HSPGs), such as perlecan, regulate SMC growth in animal models by modulating heparin-binding mitogens. Since perlecan is expressed at low levels in human atherosclerosis, we speculated that the effect of heparan sulfate (HS) in human disease was rather influenced by HS degradation and investigated the expression of heparanase (HPSE) in human carotid endarterectomies.
  
  
  RESULTS
  Gene expression analysis from 127 endarterectomies in the BiKE database revealed increased expression of HPSE in carotid plaques compared with normal arteries, and a further elevation in symptomatic lesions. Increased HPSE protein expression in symptomatic plaque tissue was verified by tissue microarrays. HPSE mRNA levels correlated positively with expression of inflammatory markers IL-18, RANTES and IL-1β, and also T-cell co-stimulatory molecules, such as B7.2, CD28, LFA-1 and 4-1BB. Previously reported single nucleotide polymorphisms within HPSE were associated with differential mRNA expression in plaques. Immunohistochemistry revealed that inflammatory cells were major producers of HPSE in plaque tissue. HPSE immunoreactivity was also observed in SMCs adjacent to the necrotic core and was co-localized to deposits of fibrin.
  
  
  CONCLUSIONS
  This study demonstrates increased expression of HPSE in human atherosclerosis associated with inflammation, coagulation and plaque instability. Since HS can regulate SMC proliferation and influence plaque stability, the findings suggest that HPSE degradation of HS take part in the regulation of SMC function in human atherosclerosis.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, SE-171 76 Stockholm, Sweden. Cecilia.Osterholm.Corbascio@ki.se
authors.forename: C
authors.initials: C
authors.lastname: Osterholm
authors.forename: L
authors.initials: L
authors.lastname: Folkersen
authors.forename: M
authors.initials: M
authors.lastname: Lengquist
authors.forename: F
authors.initials: F
authors.lastname: Pontén
authors.forename: T
authors.initials: T
authors.lastname: Renné
authors.forename: Jp
authors.initials: J
authors.lastname: Li
authors.forename: U
authors.initials: U
authors.lastname: Hedin
mesh_terms: D000328:Adult; D002340:Carotid Artery Diseases / Q000201:enzymology* / Q000235:genetics; D005786:Gene Expression Regulation; D005966:Glucuronidase / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D000099175:Heparanase