Heparan sulfate proteoglycans mediate Aβ-induced oxidative stress and hypercontractility in cultured vascular smooth muscle cells

Molecular Neurodegeneration
Matthew R ReynoldsGregory J Zipfel

Abstract

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. 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 gly...Continue Reading

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Citations

May 17, 2017·Antioxidants & Redox Signaling·Madalina-Viviana NastaseLiliana Schaefer
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Aug 24, 2019·The Anatomical Record : Advances in Integrative Anatomy and Evolutionary Biology·Ningxin GaoYuxin Ma

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Methods Mentioned

BETA
enzyme-linked immunosorbent assay
electrophoresis
immunoprecipitation
PCR
size exclusion chromatography
light microscopy

Software Mentioned

KC4
Image J

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