Interaction between BMP9/10 and Rho kinase in vascular abnormalities of scleroderma and pulmonary hypertension

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K17903
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: International University of Health and Welfare (2020-2021); The University of Tokyo (2019)
• Principal Investigator: TOYAMA TETSUO 国際医療福祉大学, 国際医療福祉大学成田病院, 講師 (30757513)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: GATA6 / BMP10 / Fli1 / ファスジル

Outline of Final Research Achievements

GATA6 deficiency in human pulmonary artery endothelial cells, which decreased antioxidants and affected mitochondrial function to increase ROS production, induced pulmonary hypertension in C57BL/6 mice, whose lungs were impaired by oxidative stress. GATA6 deficiency in vascular endothelial cells resulted in that in vascular smooth muscle cells via some humoral factors, which can account for aberrant cell proliferation of smooth muscle cells, resulting in muscularization of pulmonary arteries. BMP10 induces GATA6 expression, but in turn GATA6 expression modulated BMP10 receptor expression. Insufficient GATA6 expression deteriorated production of BMP10 receptor components like BMPR2, ActRIIB, ALK1, and endoglin. Serum BMP10 concentrations of patients with scleroderma was decreased compared to those of healthy controls. Right atrium of mice under hypoxia condition produced less amount of BMP10.

Free Research Field

全身性強皮症

Academic Significance and Societal Importance of the Research Achievements

全身性強皮症は血管障害と皮膚および内臓の線維化、免疫異常を特徴とする自己免疫疾患であり、重症例では生命を脅かす場合も少なくない。しかし、現時点では全身性強皮症に対し十分な効果を持つ治療薬は未だなく、指定難病となっている。
本研究において、全身性強皮症患者の血清BMP10の低下が、GATA6の恒常的低下につながり、血管障害を引き起こしていることが示唆された。一方ファスジルは血管障害を改善する作用が示され、全身性強皮症の治療への大きな手掛かりとなりうる。