2022 Fiscal Year Final Research Report

The mechanism of the transformation of smooth muscle cells in familial thoracic aortic aneurysm and dissection (FTAAD) of point mutation of myosin heavy chain, Myh11,

Research Project

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Project/Area Number	19K08548
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 53020:Cardiology-related
Research Institution	Jichi Medical University
Principal Investigator	Hayakawa Tomoko 自治医科大学, 医学部, 助教 (30420821)
Co-Investigator(Kenkyū-buntansha)	永井良三自治医科大学, 医学部, 学長 (60207975) 今井靖自治医科大学, 医学部, 教授 (20359631) 相澤健一自治医科大学, 医学部, 准教授 (70436484)
Project Period (FY)	2019-04-01 – 2023-03-31
Keywords	平滑筋細胞 / 動脈硬化 / 形質転換
Outline of Final Research Achievements	We had successfully established a culture system for inducing smooth muscle differentiation and transition from synthetic to contractile smooth muscle cells using mouse iPS cells, and identified the histone modification enzyme Nsd1 as a regulator of transformation. In this study, we analyzed the molecules that act between Nsd1 repression and Myh11 upregulation. bHLH-type transcription factors were found to act downstream of Nsd1 and induce Myh11 upregulation. bHLH-type transcription factors were focused on and their expression was repressed in cultured smooth muscle cells, and the results showed that Nsd1 Myh11 expression was upregulated in cultured smooth muscle cells, similar to the suppression of Nsd1. This indicates that the bHLH transcription factors are important as genes that regulate Myh11 expression downstream of Nsd1.
Free Research Field	循環器
Academic Significance and Societal Importance of the Research Achievements	動脈硬化に起因する虚血性心疾患や脳卒中は、主要な死因の一つである。脱分化した血管平滑筋細胞は、動脈硬化や大動脈瘤病変で観察され、血管疾患を促進する。Myh11は、平滑筋細胞の分化において最も成熟したときに強く発現するが、脱分化にともないMyh11発現は急激に低下する。本研究は、Myh11発現を制御するエピジェネティックな因子であるNsd1の作用を解析することで、動脈硬化が惹起されるメカニズムが解明される。今回、in vitroの系でbHLHs因子群がNsd1の下流として作用することがわかったため、これら因子群が動脈硬化の創薬のターゲットになる可能性が期待される。