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

Molecular Neurodegeneration

Gregory J. Zipfel⁴  Byung Hee Han¹  Guojun Bu²  Marc Diamond³  Hans H. Dietrich⁵  Phillip B. Verghese⁴  Brandon B. Holmes⁴  Tej D. Azad⁵  Itender Singh⁵  Matthew R. Reynolds⁵ 

[1] Department of Pharmacology, AT Still University Health Sciences, Kirksville, Missouri, USA;Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA;Center for Alzheimer’s and Neurodegenerative Diseases, UT Southwestern, Dallas, Texas, USA;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;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 63110, Missouri, USA

关键词: Heparin;    Heparinase;    Oxidative stress;    Reactive oxygen species;    Cerebrovascular dysfunction;    Vascular smooth muscle cells;    Alzheimer’s disease;    Heparan sulfate proteoglycans;   

Others  :  1235647
DOI  :  10.1186/s13024-016-0073-8

 received in 2015-02-03, accepted in 2016-01-12,  发布年份 2016

【 摘 要 】

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.

【 授权许可】

   
2016 Reynolds et al.

【 图 表 】

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