Analysis of the roles and interaction of various cells including myofibroblasts involved in fibrosis after myocardial infarction

2020 Fiscal Year Final Research Report

• Project/Area Number: 17H01525
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pharmacology in pharmacy
• Research Institution: Kyushu University
• Principal Investigator: KUROSE HITOSHI 九州大学, 薬学研究院, 教授 (10183039)
• Co-Investigator(Kenkyū-buntansha): 長坂 明臣 九州大学, 薬学研究院, 助教 (10723877) ; 仲矢 道雄 九州大学, 薬学研究院, 准教授 (80464387)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Keywords: 薬理学 / シグナル伝達 / 循環器・高血圧 / 免疫学 / 細胞外微小環境

Outline of Final Research Achievements

Lesion of the heart after myocardial infarction is compensated by collagen. However, excess deposition of collagen is called as fibrosis that is a target of the treatment. Collagen is produced by myofibroblasts. Myocardial infarction results in death of cells at ischemic area, which causes inflammation. Inflammation is induced in parallel to progression of fibrosis that is controlled by myofibroblasts. Then, mechanistic analysis of inflammation is thought to be important to treat fibrosis. In addition to inflammation, concentration of proton is known to increase under the ischemic conditions. However, the physiological meaning has not been analyzed. In this project, importance of infiltration of leukocytes to ischemic area, the roles of proton-sensing receptor in myocardial infarction and receptor-mediated intracellular signaling were studied. Then, the association of these responses with fibrosis was evaluated.

Free Research Field

分子循環薬理学

Academic Significance and Societal Importance of the Research Achievements

(1)筋線維芽細胞への分化を制御する因子として、細胞骨格に作用するドレブリンを見出した。ドレブリンの効果はSmad3およびRho/MRTF/SRF経路を介していた。(2)ロイコトリエンB4受容体が梗塞後の白血球の浸潤に大きな役割を持つこと、炎症を抑制すると線維化や心機能の低下が抑制されることを示した。(3)内皮細胞のpH感知性受容体は活性化されると接着因子の発現を増加させ、好中球の浸潤を促進し炎症を誘起させた。炎症が抑制されると線維化も抑制されたことから、炎症の抑制が線維化の進行を阻害すること、梗塞後の炎症にかかわる分子が線維化治療薬のターゲットになることを示した。