Progression of atherosclerosis by enhanced macrophage foam cell formation by matricryptic site of tenascin-C

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08606
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Tokyo University of Science, Yamaguchi (2018-2019); Tokyo University of Science (2017)
• Principal Investigator: Iyoda Takuya 山陽小野田市立山口東京理科大学, 薬学部, 准教授 (80465715)
• Co-Investigator(Kenkyū-buntansha): 中川 嘉 筑波大学, 国際統合睡眠医科学研究機構, 准教授 (80361351)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: マクロファージ / 動脈硬化 / 慢性炎症 / 細胞接着 / テネイシン-C

Outline of Final Research Achievements

Although enhanced expression of tenascin(TN)-C is frequently observed in atherosclerotic lesion, pathological role of TN-C in progression of atherosclerosis is still unknown. In this study, we focused into “region X” in TN-C molecule, and found that the ability of this region to elicit pro-atherosclerotic phenotypes from not only macrophages but vascular smooth muscle cells(VSMC). Foam cell formation was enhanced by adding region X to macrophage cell culture. Exposure to region X in high dose led VSMC to apoptotic cell death, whereas acceleration of TN-C expression was induced by low dose of region X. Moreover, we demonstrated that the progression of atherosclerosis in model animals are significantly suppressed by injection of peptide Y, which could attenuate region X's bioactivity. These results suggest that region X might be a promising target for clinical atherosclerosis treatment. Peptide Y should be a powerful candidate for a new anti-atherosclerosis drug.

Free Research Field

細胞接着、分子病態学、自然免疫

Academic Significance and Societal Importance of the Research Achievements

動脈硬化を含む各種慢性炎症性病態の多くでは tenascin(TN)-Cの高発現が認められるが、その生理・病理学的意義には未だ不明な点が多い。また動脈硬化治療においては有効な治療薬としてスタチンが確立しているが、本剤が不適な患者も一定数居り、新たな治療アプローチの創生が求められている。本課題の成果はTN-C内の一部活性領域Xが動脈硬化の病態形成に重要な役割を担うことを示し、この領域の無力化により動脈硬化病態の改善が可能であることを示した。新たな動脈硬化治療法の提起と同時に、病態促進的なTN-Cの正体として領域Xに注目する意義を提起した。