The molecular mechanisms underlying release and signaling of platelet in the systemic vascular dysfunction of diabetes

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06878
• 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): 2021-04-01 – 2024-03-31
• Keywords: 糖尿病 / 血管内皮細胞機能 / 血小板 / 細胞外小胞

Outline of Final Research Achievements

The platelets and platelet derived factor have been described as biological vectors of vascular diseases in diabetic pathologies. I found that 1) vascular endothelial dysfunction in diabetic states indicate involvement of a novel platelet-derived microparticle (MP) and factor; the resultant MPs aggravate endothelial dysfunction by regulating ERK signaling, endothelial nitirc oxide synthase (eNOS) expression, caveolin-1 expression in mice and rats aortas. 2) that the release and adhesion properties of MPs can be partially obstructed by esaxerenone (mineralocorticoid receptors blocker) via the ERK-ICAM-1 signaling pathway, which clarifies the other functions beyond the anti-hypertensive effects of esaxerenone. In diabetic mellitus, ERK-inhibitor and mineralocorticoid receptors blocker may offer effective therapeutic approaches for treating endothelial dysfunction, by reducing numbers of circulating MPs or blocking their effects by inhibiting ERK1/2 activation and ICAM expression.

Free Research Field

糖尿病性血管障害

Academic Significance and Societal Importance of the Research Achievements

糖尿病性血管障害において、血小板と血管細胞は、様々な放出因子、接着により相互に影響し合い、初期病変から、動脈硬化などの発症・進展まで広く作用している可能性が高いが、この血管細胞機能と血小板機能を直接ターゲットとした治療薬・予防薬はほぼない。本研究から、糖尿病性血管内皮細胞機能障害と、血小板、血小板由来 MPの相関性を明らかにし、この増悪化した因子における血管内皮細胞への障害機序、接着機序を明らかにし、さらに糖尿病動物への、ERK阻害薬、ミネラルコルチコイド受容体拮抗薬や抗酸化薬の慢性投与は、これらの異常を改善し、糖尿病性血管障害を改善することを明らかにした。