Amyloid β peptide-induced inhibition of endothelial nitric oxide production involves oxidative stress-mediated constitutive eNOS/HSP90 interaction and disruption of agonist-mediated Akt activation

Abstract

BackgroundAmyloid β (Aβ)-induced vascular dysfunction significantly contributes to the pathogenesis of Alzheimer’s disease (AD). Aβ is known to impair endothelial nitric oxide synthase (eNOS) activity, thus inhibiting endothelial nitric oxide production (NO).MethodIn this study, we investigated Aβ-effects on heat shock protein 90 (HSP90) interaction with eNOS and Akt in cultured vascular endothelial cells and also explored the role of oxidative stress in this process.ResultsTreatments of endothelial cells (EC) with Aβ promoted the constitutive association of HSP90 with eNOS but abrogated agonist (vascular endothelial growth factor (VEGF))-mediated HSP90 interaction with Akt. This effect resulted in blockade of agonist-mediated phosphorylation of Akt and eNOS at serine 1179. Furthermore, Aβ stimulated the production of reactive oxygen species in endothelial cells and concomitant treatments of the cells with the antioxidant N-acetyl-cysteine (NAC) prevented Aβ effects in promoting HSP90/eNOS interaction and rescued agonist-mediated Akt and eNOS phosphorylation.ConclusionsThe obtained data support the hypothesis that oxidative damage caused by Aβ results in altered interaction of HSP90 with Akt and eNOS, therefore promoting vascular dysfunction. This mechanism, by contributing to Aβ-mediated blockade of nitric oxide production, may significantly contribute to the cognitive impairment seen in AD patients.

Edaravone protects rats and human pulmonary alveolar epithelial cells against hyperoxia injury: heme oxygenase-1 and PI3K/Akt pathway may be involved

“…that derived from increased eNOS expression, but without peroxynitrite (ONOO-) generation [44]. NO can sequentially affect the Akt and HO-1 systems profoundly [45,46]. A serious limitation of the present study is that the interaction between edaravone, eNOS, NO and the Akt/HO-1 pathway is not investigated.…”

VEGFR1 and VEGFR2 in Alzheimer’s Disease

“…In addition, further work is needed to determine precisely why this signaling pathway does not function normally. decreased cholinergic innervation of intracerebral bloodvessels [10,11], reduced NO production [12][13][14][15] and an increase in vasoconstrictors EDN1 [16,19] and AngII, through upregulation of angiotensin-converting enzyme (ACE)-1 and downregulation of ACE-2 [17,18]) may all contribute to reduced cerebral blood flow (CBF). Reduced tissue oxygenation leads to increased VEGF [3,[29][30][31][32] that is not accompanied by an increase in endothelial von Willebrand factor (vWF) level and microvessel density [3].…”

“…Vessel wall abnormalities such as cerebral amyloid angiopathy (CAA) and arteriolosclerosis, may play a part in the hypoperfusion but its timing and distribution suggest that other factors are more important contributors. These include cholinergic denervation [10,11], reduced production of nitric oxide [12][13][14][15], and an increase in the intracerebral production of vasoconstrictors such as endothelin I and angiotensin II [16][17][18][19].…”

Rho‐associated protein kinases as therapeutic targets for both vascular and parenchymal pathologies in Alzheimer's disease

“…; Lamoke et al . ). Overall activity of eNOS thus receives negative input from both Aβ and ROCK1/ROCK2 activity.…”