Elucidation of gene expression regulation of ADAMTS13 and correlation with pathogenesis of thrombosis

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17878
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: Mishima Yuichi 国立研究開発法人国立循環器病研究センター, 研究所, 客員研究員 (90713876)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: ADAMTS13 / 肝星細胞 / PDE阻害剤

Outline of Final Research Achievements

ADAMTS13 is the protease that specifically cleaves vWF, and preventing excessive blood clotting. It is unclear that how expression of ADAMTS13 is regulated. ADAMTS13 is secreted from hepatic stellate cell of liver. Upon liver injury, HSC are activated with the conversion of quiescent HSC to fibrogenic cells. Activated HSC are shown that secretions of ADAMTS13 decrease in blood. IBMX is PDE inhibitor of therapeutic drug candidates for liver fibrogenesis and it increase transcription of ADAMTS13 in Lx2 cells. To investigate whether degradation of cAMP or cGMP by IBMX increases ADAMTS13 transcription, cAMP or cGMP directly were added to Lx2. In consequence, transcription of ADAMTS13 was induced by cAMP. cAMP is a second messenger and promote activation of PKA. Lx2 cells containing IBMX exposed to PKA inhibitor, and subsequently downregulate the transcription of ADAMTS13. These results suggest that the cAMP-PKA signaling pathway regulate ADAMTS13 transcription.

Free Research Field

血栓止血

Academic Significance and Societal Importance of the Research Achievements

ADAMTS13の遺伝子異常や活性阻害抗体の出現は、細血管内で血小板の凝集塊ができる血栓性血小板減少性紫斑病（TTP）の病因となる。ADAMTS13は血液凝固応答に関して重要な役割を果たすので、その遺伝子発現制御も重要になる。ADAMTS13の遺伝子発現制御が明らかになれば、その遺伝子発現制御にかかわる因子を標的とした治療薬を用いることができるので治療方法の選択肢が広がる可能性がある。