The molecular mechanisms underlying release and signaling of extracellular vesicles in the vascular dysfunction of metabolic disorder

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06974
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Hoshi University
• Principal Investigator: Kobayashi Tsuneo 星薬科大学, 薬学部, 教授 (90339523)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 細胞外小胞 / 血管障害 / 代謝性疾患 / 糖尿病

Outline of Final Research Achievements

Extracellular vesicles(EVs) have been described as biological vectors of vascular diseases in other pathologies. I found that 1) indoxyl sulfate, Advanced Glycation End Products, and UTP directly affects vascular function, especially, endothelium-dependent vasorelaxation ;2) GLP-1 causes vascular relaxation in diabetic aorta through GLP-1-dependent beta-arrestin2 recruitment ;3)extracellular signal-regulated kinases (ERK)1/2 accumulated more in diabetic EVs than in control mice-derived EVs;4) diabetic EVs induced ERK1/2 activation in mice aortas;5) in vivo treatment with ERK-inhibitor ameliorates vascular endothelial dysfunction in diabetic mice. I propose that ERK-inhibitor may be a promising therapeutic agent for EV derived-cardiovascular complications in metabolic disorder.

Free Research Field

薬学

Academic Significance and Societal Importance of the Research Achievements

動脈硬化、脳梗塞、心筋梗塞等の血管障害は、様々な代謝性機能不全の重積による合併症であり、患者の quality of life (QOL) を著しく低下する。近年、細胞外小胞 (Extracellular vesicles: EVs) は、その血液を循環する特性や、重要な生理機能が注目されており、この機能解明と血管障害との関係を明らかにすることは、革新的な新規治療薬開発につながる。本研究により、代謝性疾患時における血管障害において、EVの阻害、EVに関するシグナル伝達の阻害は、新たな血管障害の改善アプローチに繋がることを明らかにした。