Role of mutant calreticulin in pulmonary hypertension associated with myeloproliferative neoplasm

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17532
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Fukushima Medical University
• Principal Investigator: Yokokawa Tetsuro 福島県立医科大学, 医学部, 助教 (80748773)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 肺高血圧症 / CALR変異 / 骨髄増殖性疾患

Outline of Final Research Achievements

To investigate whether the hematopoietic CALR mutation contributes to pulmonary hypertension, we applied a bone marrow transplantation (BMT) with the donor cells from Calr with a 10-bp deletion knock-in mice or control wild-type (WT) mice. The recipient mice transplanted with bone marrow cells from Calr with a 10-bp deletion knock-in mice (Del-R mice) and WT mice (WT-R mice) were exposed to chronic hypoxia to induce pulmonary hypertension. After chronic hypoxia exposure, the right ventricular pressure in the Del-R mice was significantly increased compared to that in the WT-R mice. Hematopoietic Calr mutation accelerated pulmonary artery muscularization as well as elevation of endothelin-1 expression. Macrophage infiltration was observed under chronic hypoxia. Bone-marrow derived macrophages carrying Calr mutation showed increases in endothelin-1 expression. These results indicated a novel mechanism through endothelin-1 expression in pulmonary hypertension associated with CALR mutation.

Free Research Field

肺高血圧症

Academic Significance and Societal Importance of the Research Achievements

これまで明らかではなかった、CALR変異を有する骨髄増殖性疾患における肺高血圧症発症のメカニズムを、エンドセリン1に着目して解明した。