title: Immune-Mediated Inflammation May Contribute to the Pathogenesis of Cardiovascular Disease in Mucopolysaccharidosis Type I.
abstract: BACKGROUND
  Cardiovascular disease, a progressive manifestation of α-L-iduronidase deficiency or mucopolysaccharidosis type I, continues in patients both untreated and treated with hematopoietic stem cell transplantation or intravenous enzyme replacement. Few studies have examined the effects of α-L-iduronidase deficiency and subsequent glycosaminoglycan storage upon arterial gene expression to understand the pathogenesis of cardiovascular disease.
  
  
  METHODS
  Gene expression in carotid artery, ascending, and descending aortas from four non-tolerized, non-enzyme treated 19 month-old mucopolysaccharidosis type I dogs was compared with expression in corresponding vascular segments from three normal, age-matched dogs. Data were analyzed using R and whole genome network correlation analysis, a bias-free method of categorizing expression level and significance into discrete modules. Genes were further categorized based on module-trait relationships. Expression of clusterin, a protein implicated in other etiologies of cardiovascular disease, was assessed in canine and murine mucopolysaccharidosis type I aortas via Western blot and in situ immunohistochemistry.
  
  
  RESULTS
  Gene families with more than two-fold, significant increased expression involved lysosomal function, proteasome function, and immune regulation. Significantly downregulated genes were related to cellular adhesion, cytoskeletal elements, and calcium regulation. Clusterin gene overexpression (9-fold) and protein overexpression (1.3 to 1.62-fold) was confirmed and located specifically in arterial plaques of mucopolysaccharidosis-affected dogs and mice.
  
  
  CONCLUSIONS
  Overexpression of lysosomal and proteasomal-related genes are expected responses to cellular stress induced by lysosomal storage in mucopolysaccharidosis type I. Upregulation of immunity-related genes implicates the potential involvement of glycosaminoglycan-induced inflammation in the pathogenesis of mucopolysaccharidosis-related arterial disease, for which clusterin represents a potential biomarker.
authors.affiliation: National Human Neural Stem Cell Resource, CHOC Research Institute, Orange, California, United States of America.
authors.forename: Omar
authors.initials: O
authors.lastname: Khalid
authors.affiliation: Division of Medical Genetics, Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, California, United States of America.
authors.forename: Moin U
authors.initials: MU
authors.lastname: Vera
authors.affiliation: University of California-San Diego, La Jolla, California, United States of America.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Gordts
authors.affiliation: Iowa State University College of Agriculture and Life Sciences, Ames, Iowa, United States of America.
authors.forename: N Matthew
authors.initials: NM
authors.lastname: Ellinwood
authors.affiliation: National Human Neural Stem Cell Resource, CHOC Research Institute, Orange, California, United States of America.|Sue and Bill Gross Stem Cell Research Center, University of California-Irvine, Irvine, California, United States of America.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Schwartz
authors.affiliation: Division of Medical Genetics, Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, California, United States of America.
authors.forename: Patricia I
authors.initials: PI
authors.lastname: Dickson
authors.affiliation: University of California-San Diego, La Jolla, California, United States of America.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Esko
authors.affiliation: University of California-San Diego, La Jolla, California, United States of America.|Division of Metabolic Disorders, CHOC Children's Hospital, Orange, California, United States of America.
authors.forename: Raymond Y
authors.initials: RY
authors.lastname: Wang
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D002318:Cardiovascular Diseases / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D002339:Carotid Arteries / Q000276:immunology / Q000473:pathology; D051152:Clusterin / Q000032:analysis; D004285:Dogs; D005260:Female; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D007249:Inflammation / Q000150:complications* / Q000235:genetics; D008810:Mice, Inbred C57BL; D008059:Mucopolysaccharidosis I / Q000150:complications* / Q000235:genetics
chemical_list: D051152:Clusterin