Role of Jak/SOCS within non-cardiomyocytes in cardiac remodeling and failure.

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09587
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Kurume University
• Principal Investigator: Yasukawa Hideo 久留米大学, 医学部, 准教授 (60289361)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 心筋線維化 / 拡張不全 / STAT3 / SOCS3

Outline of Final Research Achievements

In this study, we created smooth-muscle specific SOCS3 (suppressor of cytokine signaling-3) deficient mice (SOCS3-smKO), which is negative feedback regulator of JAK-STAT3 signaling pathway, and investigated the role of SOCS3 in non-cardiomyocyte in diastolic function, cardiac fibrosis, pericardial fibrosis, and post myocardial infarction heart failure. We found that SOCS3-smKO mouse exhibited a variety of phenotypes including diastolic function, pericardial fibrosis, cachexia, and hypotension. The expression of pro-fibrotic CTGF (connective tissue growth factor), PDGFb (platelet growth factor-b), and TGF (transforming growth factor) family genes including TGFb1, TGFb2, and TGFb3, were significantly increased in sm-SOCS3-KO mice hearts. Thus, smooth muscle cell-specific SOCS3 deletion induces increased pericardial fibrosis, cardiac interstitial fibrosis, and increased diastolic dysfunction in aging mice, possibly through the augmentation of pro-fibrotic growth factors.

Free Research Field

心臓病学

Academic Significance and Societal Importance of the Research Achievements

本研究ではSTAT3の負の制御因子であるSOCS3 (suppressor of cytokine signaling-3)の平滑筋特異的SOCSノックアウトマウス（SOCS3-smKOマウス）を作成し、心筋線維化、心外膜肥厚や梗塞後心不全における非心筋細胞のサイトカインシグナル制御の役割を解析した。SOCS3-smKOマウスが、加齢に伴い拡張不全、心筋線維化、心外膜肥厚、体重減少、血圧低下など多彩な表現型を確認した。これらの結果は、平滑筋細胞や線維芽細胞におけるSOCS3によるSTAT3の活性化制御が、拡張不全、心外膜肥厚、悪液質、血圧調節において重要であることを示唆している。