Title: Role of the novel cardioprotective cytokine IL-22 in left ventricular remodeling after myocardial infarction.

• Project/Area Number: 17K17074
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Emergency medicine
• Research Institution: Kurume University
• Principal Investigator: Shoichiro Nohara 久留米大学, 医学部, 助教 (20647812)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: IL-22 / 梗塞後左室リモデリング / 心破裂 / 心筋梗塞後左室リモデリング / 心筋保護

Outline of Final Research Achievements

The purpose of this study is to clarify the role of interleukin 22 (IL-22) in the pathology of post-myocardial infarction (MI) remodeling. IL-22-deficient mice (IL-22KO mice) developed a high rate of cardiac rupture after MI compared with wild-type mice (WT mice). IL-22 receptor expression was enhanced in the ventricles 3 days after MI, This result suggest that IL-22 acts on the ventricles after MI. In the heart of the IL-22KO mice, macrophages and myofibroblasts were highly exist in the ventricles 3 days after MI. Furthermore, expression of mRNA for MMP13, which is an extracellular matrix degrading enzyme, and Collagen 1 were high in the IL-22KO mice. From these results, tissue destruction and fibrosis might be promoted in the heat of the IL-22 KO mice. It is considered that IL-22 controls cell infiltration and fibrosis in post-MI ventricle and suppresses cardiac rupture.

Academic Significance and Societal Importance of the Research Achievements

本研究の結果からはIL-22が心筋梗塞後の心破裂抑制に寄与する可能性が示唆された。心筋梗塞後心破裂の発症率は高くないものの、一旦、発症すると致死的となり、予後不良な病態であるため、その意義は高いと考える。また、IL-22は梗塞後心室における細胞浸潤やECM分解および合成にも関連することが示された。経皮的冠動脈形成術により急性期死亡率は改善したものの、左室リモデリングによる慢性期の心不全発症は予後不良因子の一つであり、重要な課題である。梗塞後左室リモデリングの制御メカニズムを明らかにし、IL-22の有効性が示されれば、慢性期の心不全への発展を予防する新たな治療戦略の発展に役立つことが期待される。

Research Products

• [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
  • Int'l Joint Research
• [Presentation] Interleukin-22 Delition 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: 第83回日本循環器学会学術集会
• [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
• [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] 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] Genetic deletion of IL-22 increased cardiac rupture after myocardial infarction in mice (2019)
  • Author(s): Mai Yamamoto, Shoichiro Nohara, Hideo Yasukawa, Jinya Takahashi, Tomoko Sasaki, Koutatsu Shimozono, Tatsuhiro Shibata, Toshiyuki Yanai, Kouta Okabe, Kazutoshi Mawatari, Yoshihiro Fukumoto
  • Organizer: Europian Society of Cardiology 2019 Congress
  • Int'l Joint Research
• [Presentation] Interleukin-22 Deletion Promotes Cardiac Rupture after Acute Myocardial Infarction in Mice (2018)
  • Author(s): Mai. Yamamoto, Shoichiro Nohara, Hideo Yasukawa, Jinya Takahashi, Koutatsu Shimozono, Kazutoshi Mawatari, Takanobu Nagata, Tomoko Sasaki, Tatsuhiro Shibata, Toshiyuki Yanai, Yoshihiro Fukumoto
  • Organizer: Europian Society of Cardiology 2018 Congress
  • Int'l Joint Research
• [Presentation] Lack of Interleukin-22 Increases Cardiac Rupture After Myocardial Infarction in Mice. (2018)
  • Author(s): Mai Yamamoto, Shoichiro Nohara, Hideo Yasukawa, Jinya Takahashi, Tomoko Sasaki, Koutatsu Shimozono, Tatsuhiro Shibata, Toshiyuki Yanai, Kouta Okabe, Kazutoshi Mawatari, Yoshihiro Fukumoto
  • Organizer: American Heart Association Scientific Sessions Meeting
  • Int'l Joint Research
• [Presentation] Interleukin-22 Deletion Promotes Cardiac Rupture after Acute Myocardial Infarction in Mice (2018)
  • Author(s): Mai Yamamoto, Shoichiro Nohara, Hideo Yasukawa, Jinya Takahashi, Tomoko Sasaki, Koutatsu Shimozono, Tatsuhiro Shibata, Toshiyuki Yanai, Kouta Okabe, Kazutoshi Mawatari, Takanobu Nagata, Yoshihiro Fukumoto
  • Organizer: 第83回 日本循環器学学術集会
• [Presentation] Interleukin-22 deletion promotes cardiac rupture after acute myocardial infarction in mice (2018)
  • Author(s): Mai. Yamamoto, Shoichiro Nohara, Hideo Yasukawa, Jinya Takahashi, Koutatsu Shimozono, Kazutoshi Mawatari, Takanobu Nagata, Tomoko Sasaki, Tatsuhiro Shibata, Toshiyuki Yanai, Yoshihiro Fukumoto
  • Organizer: Europian Society of Cardiology 2018 Congress
• [Presentation] IL-10 Family Cytokine IL-22 Directly Activates Myocardial STAT3 Signaling Pathway and Prevents Myocardial Ischemia-Reperfusion Injury (2018)
  • Author(s): Jinya Takahashi, Mai Yamamoto, Hideo Yasukawa, Takanobu Nagata, Koutatsu Shimozono, Shoichiro Nohara, Toshiyuki Yanai, Daisuke Fukui, Tomoko Sasaki, Tatsuhiro Shibata, Kazutoshi Mawatari, Yoshihiro Fukumoto
  • Organizer: The 82nd Annual Scientific Meeting of the Japanese Circulation Society