Role of Pin1 in the development of pulmonary hypertension and therapeutic application

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H05220
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: University of Tsukuba
• Principal Investigator: SAKAI Satoshi 筑波大学, 医学医療系, 講師 (30282362)
• Co-Investigator(Kenkyū-buntansha): 内田 隆史 東北大学, 農学研究科, 教授 (80312239) ; 柳川 徹 筑波大学, 医学医療系, 教授 (10312852) ; 正田 純一 筑波大学, 医学医療系, 教授 (90241827)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 肺高血圧症 / プロリン異性化酵素 / 肺動脈血管内皮細胞 / 内皮型一酸化窒素合成酵素

Outline of Final Research Achievements

We investigated the pathophysiological roles of peptidyl prolyl isomerase 1 (Pin1) in the development of pulmonary hypertension (PH). We generated hypoxia-induced PH model in Pin1-knockout mice (KO). Although wild type mice developed PH by hypoxia, KO did not develop. We hypothesized that Pin1 contributes to the injury of pulmonary arterial endothelial cell (PAEC); we performed in vitro experiments. Phosphorylated eNOS molecule was significantly increased by knockdown of Pin1; however, it did not differ by overexpression of Pin1. Apoptosis of PAEC was significantly suppressed by Pin1 knockdown; however, it was augmented by Pin1 overexpression. These findings suggests that Pin1 plays a role in exaggerating PH, partly via endothelial cell dysfunction in pulmonary arteries.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

難治性疾患である肺動脈性肺高血圧症の病態をPin1というユニークな分子を通して解明しようとする研究であり、得られた結果は国内外を通しても初めてのものである。Pin1は肺動脈血管内皮細胞の内皮機能抑制と細胞死促進を介して肺高血圧を促進していることが明らかになった。肺動脈性肺高血圧症の治療効果は限定的であることから、Pin1抑制が新たな治療法として今後追加される可能性を提示できたものと考えられる。