Relationship between advanced glycation endproducts and chronic inflammation in diabetic vasculopathy

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06861
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48020:Physiology-related
• Research Institution: Hoshi University
• Principal Investigator: Matsumoto Takayuki 星薬科大学, 薬学部, 准教授 (30366835)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 終末糖化産物 / 血管収縮反応 / 血管弛緩反応 / 内皮機能障害 / 糖尿病 / 細胞外核酸 / 腸内細菌由来物質

Outline of Final Research Achievements

Vascular dysfunction plays important roles in the initiation and development of diabetic complications. Accumulation of advanced glycation endproducts (AGEs), chronic inflammation and elevated gut-derived substances may induce vascular dysfunction. We found that augmentation of uridine dinucleotide-induced contraction and suppression of noradrenaline-induced contraction were seen in rat carotid arteries by acute and chronic AGEs exposure, respectively, TLR4 inhibitor augments endothelium-dependent relaxation in rat superior mesenteric arteries (SMAs), indoxyl sulfate impairs endothelium-dependent relaxation in aorta and SMAs via reduction of nitric oxide signaling, and trimethylamine N-oxide specifically impairs endothelium-derived hyperpolarizing factor-induced relaxation in femoral arteries but not SMAs. These results suggest that regulations of AGEs, TLRs, gut-derived substances are important strategies against diabetic vasculopathy.

Free Research Field

病態生理学

Academic Significance and Societal Importance of the Research Achievements

糖尿病性血管合併症は、全身で生じ得るが、様々な動脈での機能障害は未だ不明である。本研究では、様々な手法を駆使して、糖尿病時に蓄積する終末糖化産物、慢性炎症の鍵分子のトル様受容体、腸内細菌由来物質に着目し、血管機能への直接的な影響を明らかとした。さらに、血管機能重要な内皮細胞、平滑筋細胞における情報伝達機構も明らかとし、動脈部位特異的に生じる機能障害を分子レベルで解明することで、糖尿病性合併症の臓器別制御の分子基盤の一端を確立した。糖尿病は慢性疾患であり、様々な臓器機能不全からquality of life (QOL) が低下するが、本研究の成果が、QOL維持への戦略確立に繋がると確信する。