Impacts of Local Macrophage Proliferation on Atherosclerotic Plaque Progression and Obesity-associated Adipose Tissue Inflammation.

• Project/Area Number: 25461361
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kumamoto University
• Principal Investigator: Senokuchi Takafumi 熊本大学, その他の研究科, 助教 (00530320)
• Co-Investigator(Kenkyū-buntansha): MATSUMURA Takeshi 熊本大学, 医学部付属病院, 講師 (20398192)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: マクロファージ増殖 / 動脈硬化 / インスリン抵抗性 / 脂肪浸潤マクロファージ / 動脈硬化症

Outline of Final Research Achievements

To verify the direct evidence of involvement of Mφ proliferation in atherosclerosis and adipose tissue inflammation, we have generated Tg mice whose Mφ proliferation is specifically suppressed by the macrophage-specific p27kip expression. The atherosclerotic plaque formation was significantly reduced by Mφ growth inhibition. Mφs were less accumulated and the necrotic core formation was significantly decreased in Tg mice. The HFD-fed Tg showed improved insulin sensitivity. The crown-like structure formations was significantly reduced in Tg along with decreased inflammatory cytokine expression in adipose tissue.
The excess inflammatory responses in the atherosclerotic lesion and the adipose tissue were ameliorated by Mφ growth inhibition. The local Mφ proliferation could be the common pathophysiological feature in the progression of atherosclerosis and dietary-induced insulin resistance.

Research Products

• [Journal Article] Sirt7 Contributes to Myocardial Tissue Repair by Maintaining Transforming Growth Factor-β Signaling Pathway (2015)
  • Author(s): Araki S, Izumiya Y, Rokutanda T, Ianni A, Hanatani S, Kimura Y, Onoue Y, Senokuchi T, Yoshizawa T, Yasuda O, Koitabashi N, Kurabayashi M, Braun T, Bober E, Yamagata K, Ogawa H
  • Journal Title: Circulation Volume: 132(12) Issue: 12 Pages: 1081-1093
  • DOI: 10.1161/circulationaha.114.014821
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Statins meditate anti-atherosclerotic action in smooth muscle cells by peroxisome proliferator-activated receptor-γ activation. (2014)
  • Author(s): Fukuda K, Matsumura T, Senokuchi T, Ishii N, Kinoshita H, Yamada S, Murakami S, Nakao S, Motoshima H, Kondo T, Kukidome D, Kawasaki S, Kawada T, Nishikawa T, Araki E
  • Journal Title: Biochem Biophys Res Commun Volume: 457 Issue: 1 Pages: 23-20
  • DOI: 10.1016/j.bbrc.2014.12.063
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] SIRT7 controls hepatic lipid metabolism by regulating the ubiquitin-proteasome pathway. (2014)
  • Author(s): Yoshizawa T, Karim Md. F, Sato Y, Senokuchi T, Miyata K, Fukuda T, Go C, Tasaki M, Uchimura K, Kadomatsu T, Tian Z, Smolka C, Sawa T, Kakeya M, Tomizawa K, Ando Y, Araki E, Akaike T, Braun T, Oike Y, Bober E, Yamagata K.
  • Journal Title: Cell Metab. Volume: 9 Issue: 4 Pages: 712-721
  • DOI: 10.1016/j.cmet.2014.03.006
  • Peer Reviewed / Open Access
• [Presentation] インスリン抵抗性および動脈硬化発症・進展におけるマクロファージ増殖の意義の検討 (2015)
  • Author(s): 瀬ノ口隆文、山田沙梨恵、松村 剛、本島寛之、石井規夫、 福田一起、村上彩子、守田雄一郎、西川武志、荒木栄一
  • Organizer: 第53回日本糖尿病学会 九州地方会
  • Place of Presentation: 福岡市
  • Year and Date: 2015-11-27
• [Presentation] Targeted Disruption of Macrophage Proliferation Ameliorates Atherosclerotic Plaque Progression and Obesity-associated Adipose Tissue Inflammation. (2015)
  • Author(s): Takafumi Senokuchi, Sarie Yamada, Takeshi Matsumura, Takeshi Nishikawa, Eiichi Araki
  • Organizer: 2016 Keystone Symposia Conference, T2 Diabetes: New Insights into Molecular Mechanisms and Therapeutic Strategies
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2015-10-25
  • Int'l Joint Research
• [Presentation] Impacts of Local Macrophage Proliferation on Atherosclerotic Plaque Progression and Obesity-associated Adipose Tissue Inflammation. (2015)
  • Author(s): Sarie Yama, Takafumi Senokuchi, Takeshi Matsumura, Takeshi Nishikawa, Eiichi Araki
  • Organizer: 75th Scientific Sessions, American Diabetes Association
  • Place of Presentation: Boston, U.S.A.
  • Year and Date: 2015-06-05 – 2015-06-09
• [Presentation] Impacts of Local Macrophage Proliferation on Atherosclerotic Plaque Progression and Obesity-Associated Adipose Tissue Inflammation (2015)
  • Author(s): Sarie Yamada, Takafumi Senokuchi, Takeshi Matsumura, Takeshi Nishikawa, Eiichi Araki
  • Organizer: American Diabetes Association 75th Scientific Sessions
  • Place of Presentation: Boston, U.S.A.
  • Year and Date: 2015-06-05
  • Int'l Joint Research
• [Presentation] インスリン抵抗性及び動脈硬化の発症・進展に対する組織浸潤マクロファージ増殖の生理学的意義の検討 (2015)
  • Author(s): 山田沙梨恵, 瀬ノ口隆文, 松村 剛, 本島寛之, 石井規夫, 木下博之, 福田一起, 西川武志, 荒木栄一
  • Organizer: 第58回日本糖尿病学会年次学術集会
  • Place of Presentation: 下関市
  • Year and Date: 2015-05-21 – 2015-05-24
• [Presentation] インスリン抵抗性及び動脈硬化の発症・進展に対する組織浸潤マクロファージ増殖の 生理学的意義の検討 (2015)
  • Author(s): 山田 沙梨恵
  • Organizer: 第58回日本糖尿病学会年次学術集会
  • Place of Presentation: 下関市
  • Year and Date: 2015-05-21
• [Presentation] インスリン抵抗性、動脈硬化の発症・進展 における組織浸潤マクロファージ増殖の 生理学的意義の検討 (2014)
  • Author(s): 瀬ノ口 隆文、山田 沙梨恵、松村 剛、 本島 寛之、西川 武志、荒木 栄一
  • Organizer: 第26回分子糖尿病学シンポジウム
  • Place of Presentation: 高知市
  • Year and Date: 2014-12-06
• [Presentation] Statin-mediated PPARγ activation in adipocytes may improve glucose tolerance in high fat-fed mice. (2014)
  • Author(s): Takafumi Senokuchi, Takeshi Matsumura, Kazuki Fukuda, Norio Ishii, Hiroyuki Kinoshita, Sarie Yamada, Saiko Murakami, Tatsuya Kondo, Hiroyuki Motoshima, Takeshi Nishikawa, Eiichi Araki
  • Organizer: 6th AASD Scientific Meeting
  • Place of Presentation: Singapore
  • Year and Date: 2014-09-21 – 2014-09-24
• [Presentation] Inhibition of Local Macrophage Growth Ameliorates Focal inflammation in the Plaque and Suppresses Atherosclerosis in ApoE-deficient Mice. (2014)
  • Author(s): Takafumi Senokuchi, Sarie Yamada, Emi Negita, Takeshi Matsumura, Takeshi Nishikawa, Eiichi Araki
  • Organizer: 9th Metabolic Syndrome, Type 2 Diabetes and Atherosclerosis Congress
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2014-09-12 – 2014-09-13
• [Presentation] 糖尿病における動脈硬化症進展の体質医学的研究 組織浸潤マクロファージ増殖の意義の検討 (2014)
  • Author(s): 瀬ノ口 隆文
  • Organizer: 第64回日本体質医学会総会
  • Place of Presentation: 大阪市
  • Year and Date: 2014-09-06 – 2014-09-07
• [Presentation] 動脈硬化病変形成におけるマクロファージ増殖の病態生理学的意義の検討 (2014)
  • Author(s): 山田 沙梨恵、瀬ノ口 隆文、松村 剛、本島 寛之、石井 規夫、木下 博之、福田 一起、西川 武志、荒木 栄一
  • Organizer: 第46回日本動脈硬化学会総会・学術集会
  • Place of Presentation: 東京都
  • Year and Date: 2014-07-10 – 2014-07-11
• [Presentation] 肥満•メタボリックシンドロームにおける 血清脂質値への コレステロール合成・吸収能の影響 (2013)
  • Author(s): 11. 瀬ノ口隆文, 松村剛, 本島寛之, 石井規夫, 木下博之, 福田一起, 金谷絢子, 佐藤恵子, 荒木栄一
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本市
• [Presentation] インスリン抵抗性マクロファージのFoxO活性化を介した アポトーシス誘導による動脈硬化進展機序の解明 (2013)
  • Author(s): 瀬ノ口隆文, 山田沙梨恵, 松村剛, 西川武志, 荒木栄一
  • Organizer: 第45回日本動脈硬化学会総会・学術集会
  • Place of Presentation: 東京都
• [Presentation] マクロファージインスリン抵抗性による動脈硬化進展機序の検討 (2013)
  • Author(s): 瀬ノ口隆文, 山田沙梨恵, 松村剛, 西川武志, 荒木栄一
  • Organizer: 第28回日本糖尿病合併症学会
  • Place of Presentation: 旭川市
• [Presentation] 肥満における血清脂質値へのコレステロール合成・吸収能の影響 (2013)
  • Author(s): 瀬ノ口隆文, 松村剛, 石井規夫, 本島寛之, 西川武志, 荒木栄一
  • Organizer: 第110回日本内科学会総会
  • Place of Presentation: 東京都