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

• 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
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 心筋線維化 / 拡張不全 / STAT3 / SOCS3 / 心筋リモデリング / サイトカイン / 心不全 / 心外膜 / 血管平滑筋細胞 / 心筋梗塞 / Jak-STAT

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.

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。

Research Products

• [Journal Article] Genetic Deletion of Socs3 in Smooth?Muscle Cells Ameliorates Aortic?Dissection in Mice (2020)
  • Author(s): Hirakata Saki、Aoki Hiroki、Ohno-Urabe Satoko、Nishihara Michihide、Furusho Aya、Nishida Norifumi、Ito Sohei、Hayashi Makiko、Yasukawa Hideo、Imaizumi Tsutomu、Hiromatsu Sinichi、Tanaka Hiroyuki、Fukumoto Yoshihiro
  • Journal Title: JACC: Basic to Translational Science Volume: 5 Issue: 2 Pages: 126-144
  • DOI: 10.1016/j.jacbts.2019.10.010
  • Peer Reviewed / Open Access
• [Journal Article] High Salt Intake Worsens Aortic Dissection in Mice (2020)
  • Author(s): Nishida Norifumi、Aoki Hiroki、Ohno-Urabe Satoko、Nishihara Michihide、Furusho Aya、Hirakata Saki、Hayashi Makiko、Ito Sohei、Yamada Hiroshi、Hirata Yuichiro、Yasukawa Hideo、Imaizumi Tsutomu、Tanaka Hiroyuki、Fukumoto Yoshihiro
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 40 Issue: 1 Pages: 189-205
  • DOI: 10.1161/atvbaha.119.313336
  • Peer Reviewed / Open Access
• [Journal Article] Interleukin-22 Directly Activates Myocardial STAT3 Signaling Pathway and Prevents Myocardial Ischemia Reperfusion Injury. (2020)
  • Author(s): Takahashi J, Yamamoto M, Yasukawa H, Nohara S, Nagata T, Shimozono K, Yanai T, Sasaki T, Okabe K, Shibata T, Mawatari K, Kakuma T, Aoki H, Fukumoto Y.
  • Journal Title: J Am Heart Assoc. Volume: 9 Issue: 8
  • DOI: 10.1161/jaha.119.014814
  • Peer Reviewed / Open Access
• [Journal Article] Role of Macrophage Socs3 in the Pathogenesis of Aortic Dissection (2018)
  • Author(s): Ohno‐Urabe Satoko、Aoki Hiroki、Nishihara Michihide、Furusho Aya、Hirakata Saki、Nishida Norifumi、Ito Sohei、Hayashi Makiko、Yasukawa Hideo、Imaizumi Tsutomu、Akashi Hidetoshi、Tanaka Hiroyuki、Fukumoto Yoshihiro
  • Journal Title: Journal of the American Heart Association Volume: 7 Issue: 2
  • DOI: 10.1161/jaha.117.007389
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 心筋梗塞後の組織修復におけるIL-22の役割 (2019)
  • Author(s): 山本真衣、安川秀雄、髙橋甚彌、野原正一郎、佐々木知子、下園弘達、柴田龍宏、楊井俊之、岡部浩太、福本義弘.
  • Organizer: 第19回日本NO学会学術集会
• [Presentation] Interleukin-22 Deletion Promotes Cardiac Rupture after Acute Myocardial infarction in Mice. (2019)
  • Author(s): Yamamoto M, Yasukawa H, Takahashi J, Shimozono K, Mawatari K, Nagata T, Nohara S, Sasaki T, Shibata T, Yanai T, Fukumoto Y.
  • Organizer: The 3rd JCS Council Forum on Basic CardioVascular Research
  • Int'l Joint Research
• [Presentation] 心筋梗塞後の創傷治癒におけるIL-22の役割. (2019)
  • Author(s): 山本真衣、安川秀雄、髙橋甚彌、野原正一郎、佐々木知子、下園弘達、柴田龍宏、楊井俊之、岡部浩太、馬渡一寿、福本義弘
  • Organizer: 第127回日本循環器学会九州地方会
• [Presentation] Increased pericardial fibrosis and cardiac dysfunction in smooth muscle cell-specific SOCS3 deficient mice (2019)
  • Author(s): Yanai T, Yasukawa H, Mawatari K, Sasaki T, Takahashi J, Nohara S, Shimozono K, Shibata T, Okabe K, Yamamoto M, Fukumoto Y
  • Organizer: ESC Congress 2019
  • Int'l Joint Research
• [Presentation] Genetic deletion of IL-22 increased cardiac rupture after myocardial infarction in mice. (2019)
  • Author(s): Yamamoto M, Yasukawa H, Takahashi J, Shimozono K, Mawatari K, Nagata T, Nohara S, Sasaki T, Shibata T, Yanai T, Fukumoto Y
  • Organizer: ESC Congress 2019
  • Int'l Joint Research
• [Presentation] Interleukin-22 deletion promotes cardiac rupture after acute myocardial infarction in mice (2018)
  • Author(s): Yamamoto M, Yasukawa H, Takahashi J, Shimozono K, Mawatari K, Nagata T, Nohara S, Sasaki T, Shibata T, Yanai T, Fukumoto Y
  • Organizer: European Society of Cardiology (ESC) Congress
  • Int'l Joint Research
• [Presentation] Lack of Interleukin-22 Increases Cardiac Rupture After Myocardial Infarction in Mice (2018)
  • Author(s): Yamamoto M, Yasukawa H, Takahashi J, Nohara N, Sasaki T, Shimozono K, Shibata T, Yanai T, Mawatari K, Nagata T, Fukumoto Y
  • Organizer: The American Heart Association, The 91th Scientific Sessions (AHA2018)
  • Int'l Joint Research
• [Presentation] IL-10 Family Cytokine IL-22 Directly Activates Myocardial STAT3 Signaling Pathway and Prevents Myocardial Ischemia-Reperfusion Injury (2018)
  • Author(s): Takahashi J, Yamamoto M, Yasukawa H, Nagata T, Shimozono K, Nohara S, Yanai T, Fukui D, Sasaki T, Shibata T, Mawatari K, Fukumoto Y
  • Organizer: 第82回日本循環器学会学術集会
  • Int'l Joint Research