The role of Notch1-TGFbeta-PIAS1 on pulmonary hypertension

2014 Fiscal Year Final Research Report

• Project/Area Number: 24591108
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Gunma University
• Principal Investigator: KOWASE Keiko 群馬大学, 医学(系)研究科(研究院), 講師 (50594264)
• Co-Investigator(Kenkyū-buntansha): KURABAYASHI Masahiko 群馬大学, 大学院医学系研究科, 教授 (00215047) ; NAKAHARA Takehiro 群馬大学, 大学院医学系研究科, 助教 (00599540)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 肺高血圧

Outline of Final Research Achievements

We have previously shown that the protein inhibitor of activated STAT (PIAS)1 promotes TGFbeta-induced activation of SMC gene expression at least in part by promoting sumoylation. Here,we tested the hypothesis that Notch1-TGFbeta-PIAS1 axis promote pulmonary artery hypertension (PAH).An siRNA specific for PIAS1 and ubc9, an E2-ligase for sumoylation, inhibited TGFbeta- and Notch1-induced expression of SMC specific genes in cultured pulmonary artery smooth muscle cells (PASMC) as determined by real-time RT-PCR. Expression of osteoprotegerine（OPG）was also inhibited by siRNA specific for PIAS1 and ubc9. Moreover,overexpression of PIAS family increased OPG promoter activity. Immunohistochemistry of model mice for hypoxia-induced pulmonary hypertension revealed colocalized expression of TGFbetaRII、Notch1 and SMC marker in pulmonary artery, whereas SUMO1 and OPG were expressed in tracheal epithelial cell. These results could indicate that Notch1-TGFbeta-PIAS1 axis participate in PAH.

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