The roles of polarization of macrophages in cardiac fibrosis

• Project/Area Number: 15K19369
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: The University of Tokyo
• Principal Investigator: Hajime Abe 東京大学, 医学部附属病院, 特任臨床医 (50746576)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 心不全 / 炎症 / マクロファージ / 心臓リモデリング / 心線維化 / 低酸素

Outline of Final Research Achievements

While macrophages seem to play a key role in cardiac remodeling, their precise functions still remain unclear. In this study, we investigated the roles of cardiac macrophages in the process of cardiac remodeling using Transverse aortic constriction (TAC) model. Macrophages can be classified into 2 broad phenotypes, namely M1 macrophages and M2 macrophages. Most of the recruited cells at day 3 were M1 macrophages and day 7 were M2 macrophages. We have previously reported that the hypoxia response transcription factor, HIF-1a, plays an essential role in M1 macrophages activation. To verify the roles of M1 macrophages in cardiac remodeling, we subsequently generated macrophage specific HIF-1a knockout mice (mHIF-1a CKO). FACS analysis revealed that M1 macrohpages accumulation was significantly decreased and more prominent cardiac fibrosis in mHIF-1a CKO mice after TAC. These results demonstrate a novel functional link between M1 macrophages and cardiac remodeling.

Research Products

• [Journal Article] Distinct Metabolic Phenotypes within Non-small Cell 1 Lung Cancer Define Selective Vulnerability to Glycolytic Inhibition of Lung Squamous Cell Carcinoma. (2017)
  • Author(s): Goodwin J, Neugent ML, Lee SY, Choe JH, Choi H, Jenkins DMR, Ruthenborg RJ, Robinson MW, Jeong JY, Wake M, Abe H, Takeda N, Endo H, Inoue M, Xuan Z, Yoo H, Chen M, Ahn JM, Minna JD, Helke KL, Singh PK, Shackelford DB, Kim JW.
  • Journal Title: Nature Commun. 2017 (印刷中). Volume: 印刷中
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Planimetry of the orifice area in aortic valve stenosis using phase-contrast cardiac magnetic resonance imaging. (2017)
  • Author(s): Abe H., Iguchi N, Utanohara Y, Takada K, Hen Y, Machida H, Takeda N, Sumiyoshi T.
  • Journal Title: Int Heart J. 2017 (印刷中) Volume: 印刷中
  • NAID: 130006321387
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] HIF-1alpha-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity (2016)
  • Author(s): Semba, H., Takeda, N., Isagawa, T., Sugiura, Y., Honda, K., Wake, M., Miyazawa, H., Yamaguchi, Y., Miura, M., Jenkins, DM., Choi, H., Kim, JW., Asagiri, M., Cowburn, AS., Abe, H., Soma, K., Koyama, K., Katoh, M., Sayama, K., Goda, N., Johnson, RS., Manabe, I., Nagai, R., Komuro, I.
  • Journal Title: Nature Communications Volume: 7 Issue: 1 Pages: 11635-11635
  • DOI: 10.1038/ncomms11635
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HIF-1α-PDK1 axis induced active glycolysis plays an essential role in macrophage migratory capacity (2016)
  • Author(s): Hiroaki , Norihiko T, Takayuki I, Yuki S, Kurara H, Masaki W, Hidenobu M, Yoshifumi Y, Masayuki M, Dana J, Hyunsung C, Jung-whan K, Masataka A, Andrew C, Hajime A, Katsura S, Katsuhiro K, Manami K, Keimon S, Nobuhito G, Randall S J, Ichiro M, Ryozo N, and Issei K
  • Journal Title: Nature Communications Volume: In press
  • Peer Reviewed / Open Access
• [Presentation] Roles of Ly6Chi monocytes hypoxia signaling in cardiac remodeling (2017)
  • Author(s): Abe H, Takeda N, Isagawa T, Semba H, Soma K, Koyama K, Wake M, Katoh M, Manabe I, Nagai R, Komuro I
  • Organizer: Keystone Symposium “Adaptations to Hypoxia in Physiology and Disease”
  • Place of Presentation: Whistler, British Columbia, Canada
  • Year and Date: 2017-03-05
  • Int'l Joint Research
• [Presentation] 心臓リモデリングにおいてLy6C highマクロファージはHIF-1α-OncostatinMシグナルを介して心保護的に作用する (2016)
  • Author(s): 安部 元,武田 憲彦,仙波 宏章,相馬 桂,小山 雄広,和氣 正樹,加藤 愛巳,中釜 悠,真鍋 一郎,永井 良三,小室 一成
  • Organizer: 第20回日本心血管内分泌代謝学会学術総会
  • Place of Presentation: 東京コンベンションホール
  • Year and Date: 2016-12-16
• [Presentation] 圧負荷後心臓リモデリングにおけるマクロファージ低酸素シグナルの役割 (2016)
  • Author(s): 安部 元, 武田 憲彦, 砂河 孝行, 仙波 宏章, 相馬 桂, 小山 雄広, 和氣 正樹, 加藤 愛巳, 中釜 悠, 真鍋 一郎, 永井 良三, 小室 一成
  • Organizer: 第39回日本高血圧学会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2016-09-30
  • Invited
• [Presentation] HIF-1α - PDK1 axis induced active glycolysis plays an essential role in macrophage migratory capacity (2016)
  • Author(s): Takeda N, Semba H, Isagawa T, Abe H, Sugiura Y, Honda K, Wake M, Kim JW, Soma K, Koyama K, Katoh M, Johnson RS, Manabe I, Nagai R and Komuro I
  • Organizer: Keystone symposium; Immunometabolism in immune function and inflammatory disease
  • Place of Presentation: Banff (Canada)
  • Year and Date: 2016-02-24
  • Int'l Joint Research
• [Presentation] Roles of Ly6Chi monocytes hypoxia signaling in cardiac remodeling (2016)
  • Author(s): Abe H, Takeda N, Semba H, Soma K, Koyama K, Wake M, Katoh M, Manabe I, Nagai R and Komuro I
  • Organizer: Keystone symposium; Immunometabolism in immune function and inflammatory disease
  • Place of Presentation: Banff (Canada)
  • Year and Date: 2016-02-22
  • Int'l Joint Research
• [Presentation] HIF-1α - Pdk1 axis induced metabolic reprogramming critically regulates macrophage function in inflammatory conditions (2016)
  • Author(s): Semba H, Takeda N, Isagawa T, Wake M, Abe H, Soma K, Koyama K, Katoh M, Manabe I, Nagai R, Takeshi Yamashita and Komuro I
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際センター（宮城県・仙台）
  • Year and Date: 2016-02-13
• [Presentation] M1マクロファージの集積遷延は腫瘍内血管の未熟化を引き起こす (2015)
  • Author(s): 相馬桂 武田憲彦 砂河孝行 安部元 仙波宏章 小山雄広 和氣正樹 加藤愛巳 真鍋一郎 永井良三 小室一成
  • Organizer: 第23回日本血管生物医学会学術集会
  • Place of Presentation: 神戸国際会議場(兵庫県・神戸市）
  • Year and Date: 2015-12-12
• [Presentation] Roles of macrophages hypoxia signaling in pressure overload-induced cardiac remodeling (2015)
  • Author(s): Abe H, Takeda N, Semba H, Soma K, Koyama K, Wake M, Katoh M, Manabe I, Nagai R and Komuro I.
  • Organizer: 第32回国際心臓研究学会日本部会
  • Place of Presentation: 神戸国際会議場(兵庫県・神戸市）
  • Year and Date: 2015-12-10
• [Presentation] Perivascular accumulation of M1 macrophages elicits the development of immature vascular formation (2015)
  • Author(s): Soma K, Takeda N, Isagawa T, Abe H, Semba H, Koyama K, Wake M, Manabe I, Nagai R and Komuro I
  • Organizer: ESC Congress2015
  • Place of Presentation: London (UK)
  • Year and Date: 2015-09-01
  • Int'l Joint Research
• [Presentation] Roles of Macrophages Hypoxia Signaling in Pressure Overload Induced Cardiac Remodeling (2015)
  • Author(s): Abe H, Takeda N, Semba H, Soma K, Koyama K, Wake M, Manabe I, Nagai R and Komuro I
  • Organizer: 第79回日本循環器学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府・大阪市)
  • Year and Date: 2015-04-25