The activity of endothelial NO synthase is suppressed by amylospheroid

2017 Fiscal Year Final Research Report

• Project/Area Number: 16K21713
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pharmacology in pharmacy; General pharmacology
• Research Institution: Foundation for Biomedical Research and Innovation
• Principal Investigator: Sasahara Tomoya 公益財団法人先端医療振興財団, その他部局等, 研究員(研究員・PDクラス) (30735345)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Keywords: アミロイドβタンパク / 血管内皮 / eNOS / アミロスフェロイド / 一酸化窒素 / 血管機能障害 / 脳アミロイド血管症 / Na+/K+-ATPase alpha 3

Outline of Final Research Achievements

Amyloid-beta have been reported to cause cerebrovascular endothelial dysfunctions, but it has not been clarified what kind of amyloid-beta oligomer elicits endothelial toxicity. Here we verified the effects of ASPD, 30-mer amyloid-beta assemblies, to eNOS activity. ASPD suppressed NO release, and phosphorylated eNOS at Thr495, suggesting eNOS inactivation. PKC inhibitor abolished ASPD-induced Thr495-eNOS phosphorylation. ASPD-induced PKC activation was inhibited by ROS scavenger. Additionally, we found that ASPD induced ROS production in mitochondria. Knockdown of ASPD-binding Na+, K+-ATPase alpha 3 inhibited ASPD-induced Thr495-eNOS phosphorylation. Using rat aortic rings, ASPD attenuated carbachol-induced vasorelaxation. In summary, we elucidated the effects of ASPD and revealed its mechanisms in cerebrovascular endothelium. Our results suggest that ASPD play roles on cerebrovascular dysfunctions by suppressing eNOS activity.

Free Research Field

循環器薬理