title: Heparan sulfate proteoglycans mediate Aβ-induced oxidative stress and hypercontractility in cultured vascular smooth muscle cells.
abstract: BACKGROUND
  Substantial evidence suggests that amyloid-β (Aβ) species induce oxidative stress and cerebrovascular (CV) dysfunction in Alzheimer's disease (AD), potentially contributing to the progressive dementia of this disease. The upstream molecular pathways governing this process, however, are poorly understood. In this report, we examine the role of heparan sulfate proteoglycans (HSPG) in Aβ-induced vascular smooth muscle cell (VSMC) dysfunction in vitro.
  
  
  RESULTS
  Our results demonstrate that pharmacological depletion of HSPG (by enzymatic degradation with active, but not heat-inactivated, heparinase) in primary human cerebral and transformed rat VSMC mitigates Aβ(1-40⁻) and Aβ(1-42⁻)induced oxidative stress. This inhibitory effect is specific for HSPG depletion and does not occur with pharmacological depletion of other glycosaminoglycan (GAG) family members. We also found that Aβ(1-40) (but not Aβ(1-42)) causes a hypercontractile phenotype in transformed rat cerebral VSMC that likely results from a HSPG-mediated augmentation in intracellular Ca(2+) activity, as both Aβ(1-40⁻)induced VSMC hypercontractility and increased Ca(2+) influx are inhibited by pharmacological HSPG depletion. Moreover, chelation of extracellular Ca(2+) with ethylene glycol tetraacetic acid (EGTA) does not prevent the production of Aβ(1-40⁻) or Aβ(1-42⁻)mediated reactive oxygen species (ROS), suggesting that Aβ-induced ROS and VSMC hypercontractility occur through different molecular pathways.
  
  
  CONCLUSIONS
  Taken together, our data indicate that HSPG are critical mediators of Aβ-induced oxidative stress and Aβ(1-40⁻)induced VSMC dysfunction.
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, Hope Center Program on Protein Aggregation and Neurodegeneration, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Campus Box 8057, 660 South Euclid Avenue, St. Louis, Missouri, 63110, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Reynolds
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, Hope Center Program on Protein Aggregation and Neurodegeneration, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Campus Box 8057, 660 South Euclid Avenue, St. Louis, Missouri, 63110, USA.
authors.forename: Itender
authors.initials: I
authors.lastname: Singh
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, Hope Center Program on Protein Aggregation and Neurodegeneration, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Campus Box 8057, 660 South Euclid Avenue, St. Louis, Missouri, 63110, USA.
authors.forename: Tej D
authors.initials: TD
authors.lastname: Azad
authors.affiliation: Department of Neurology, Washington University School of Medicine, Hope Center Program on Protein Aggregation and Neurodegeneration, Charles F. and Joanne Knight Alzheimer's Disease Research Center, St. Louis, Missouri, USA.
authors.forename: Brandon B
authors.initials: BB
authors.lastname: Holmes
authors.affiliation: Department of Neurology, Washington University School of Medicine, Hope Center Program on Protein Aggregation and Neurodegeneration, Charles F. and Joanne Knight Alzheimer's Disease Research Center, St. Louis, Missouri, USA.
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Verghese
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, Hope Center Program on Protein Aggregation and Neurodegeneration, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Campus Box 8057, 660 South Euclid Avenue, St. Louis, Missouri, 63110, USA.
authors.forename: Hans H
authors.initials: HH
authors.lastname: Dietrich
authors.affiliation: Center for Alzheimer's and Neurodegenerative Diseases, UT Southwestern, Dallas, Texas, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Diamond
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.affiliation: Department of Pharmacology, AT Still University Health Sciences, Kirksville, Missouri, USA.
authors.forename: Byung Hee
authors.initials: BH
authors.lastname: Han
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, Hope Center Program on Protein Aggregation and Neurodegeneration, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Campus Box 8057, 660 South Euclid Avenue, St. Louis, Missouri, 63110, USA. zipfelg@wustl.edu.|Department of Neurology, Washington University School of Medicine, Hope Center Program on Protein Aggregation and Neurodegeneration, Charles F. and Joanne Knight Alzheimer's Disease Research Center, St. Louis, Missouri, USA. zipfelg@wustl.edu.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Zipfel
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D019812:Heparan Sulfate Proteoglycans; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)