Heparan sulfate proteoglycans mediate Aß-induced oxidative stress and hypercontractility in cultured vascular smooth muscle cells.
Mol Neurodegener
; 11: 9, 2016 Jan 22.
Article
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| MEDLINE
| ID: mdl-26801396
ABSTRACT
BACKGROUND:
Substantial evidence suggests that amyloid-ß (Aß) 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 Aß-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 Aß(1-40â») and Aß(1-42â»)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 Aß(1-40) (but not Aß(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 Aß(1-40â»)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 Aß(1-40â») or Aß(1-42â»)mediated reactive oxygen species (ROS), suggesting that Aß-induced ROS and VSMC hypercontractility occur through different molecular pathways.CONCLUSIONS:
Taken together, our data indicate that HSPG are critical mediators of Aß-induced oxidative stress and Aß(1-40â»)induced VSMC dysfunction.
Texto completo:
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Bases de datos:
MEDLINE
Asunto principal:
Fragmentos de Péptidos
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Péptidos beta-Amiloides
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Especies Reactivas de Oxígeno
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Estrés Oxidativo
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Proteoglicanos de Heparán Sulfato
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Músculo Liso Vascular
Límite:
Humans
Idioma:
En
Revista:
Mol Neurodegener
Año:
2016
Tipo del documento:
Article
País de afiliación:
Estados Unidos