Molecular mechanism in atheroprotective effects by the enzymes that control membrane sphingolipid levels

• Project/Area Number: 16K15409
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General internal medicine(including psychosomatic medicine)
• Research Institution: Kanazawa University
• Principal Investigator: ISHIMARU KAZUHIRO 金沢大学, 医学系, 協力研究員 (70595446)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 動脈硬化 / 老年医学 / スフィンゴ脂質代謝 / 動脈硬化症 / オートファジー

Outline of Final Research Achievements

In mice in which the metabolic enzyme was systematically deleted, atherosclerotic lesions were significantly increased by loading with a cholesterol diet. And, it was thought that the enzyme present in bone marrow-derived cells, particularly macrophages, were strongly involved. This enzyme might have atheroprotective role.
After macrophages take up unnecessary or modified lipids, they change to foam cells and deposit in arterial blood vessels followed by blood flow problems. By the analysis of lipid uptake and degradation functions, lipolysis-related autophagic pathways may be mainly impaired in enzyme deleted macrophages.

Academic Significance and Societal Importance of the Research Achievements

これまでにも全世界で動脈硬化治療薬の開発が行われて来たが、未だ画期的な治療薬は作出されて来なかった。新しい治療薬の開発の為には、新しい観点からの動脈硬化形成機序を明らかにする事が重要である。本研究により、スフィンゴ脂質代謝を制御する鍵酵素が持つ抗動脈硬化作用がオートファジー制御という新しい観点から発揮される事が判明した。これらは今後、新規動脈硬化治療法の開発基盤への有益な情報提供となる。

Research Products

• [Journal Article] The class II phosphoinositide 3-kinases PI3K-C2α and PI3K-C2β differentially regulate clathrin-dependent pinocytosis in human vascular endothelial cells. (2019)
  • Author(s): Aung KT, Yoshioka K, Ishimaru K, Aki S, Takuwa N, and Takuwa Y.
  • Journal Title: Journal of Physiological Sciences Volume: 69 Issue: 2 Pages: 263-280
  • DOI: 10.1007/s12576-018-0644-2
  • Peer Reviewed / Open Access
• [Journal Article] Class II PI3Ks α nad β are required for Rho-dependent uterine smooth muscle contraction and parturition in mice. (2019)
  • Author(s): Sarker AK, Aki S, Yoshioka K, Kuno K, Okamoto Y, Ishimaru K, Takuwa N, and Takuwa Y.
  • Journal Title: Endocrinology Volume: 160 Issue: 1 Pages: 235-248
  • DOI: 10.1210/en.2018-00756
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sphingosine-1-phosphate receptor-2 facilitates pulmonary fibrosis through potentiating IL-13 pathway in macrophages. (2018)
  • Author(s): Zhao J, Okamoto Y, Asano Y, Ishimaru K, Aki S, Yoshioka K, Takuwa N, Wada T, Inagaki Y, Takahashi C, Nishiuchi T, Takuwa Y.
  • Journal Title: PLoS One Volume: 13 Issue: 5 Pages: e0197604-e0197604
  • DOI: 10.1371/journal.pone.0197604
  • NAID: 120006605152
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MTMR4, a phosphoinositide specific 3’-phosphatase, regulates TFEB activity and the endocytic and autophagic pathways. (2018)
  • Author(s): Pham HQ, Yoshioka K, Mohri H, Nakata H, Aki S, Ishimaru K, Takuwa N, and Takuwa Y.
  • Journal Title: Genes to Cells Volume: 23 Issue: 8 Pages: 670-687
  • DOI: 10.1111/gtc.12609
  • NAID: 120006621947
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] iNOS as a Driver of Inflammation and Apoptosis in Mouse Skeletal Muscle after Burn Injury: Possible Involvement of Sirt1 S-Nitrosylation-Mediated Acetylation of p65 NF-κB and p53. (2017)
  • Author(s): Nakazawa H, Chang K, Shinozaki S, Yasukawa T, Ishimaru K, Yasuhara S, Yu YM, Martyn JA, Tompkins RG, Shimokado K, Kaneki M
  • Journal Title: PLoS One Volume: 12(1) Issue: 1 Pages: e0170391-e0170391
  • DOI: 10.1371/journal.pone.0170391
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Myotubularin-related protein 4 (MTMR4), a phosphoinositide 3'-phosphatase, regulates endolysosome integrity and autophagy flux in human lung alveolar epithelial A549 cells (2018)
  • Author(s): Pham Quynh Hoa, Yoshioka Kazuaki, Azadul Sarker Kabir, Aung Thuzar Khin, Islam Shahidul, Aki Sho, Ishimaru Kazuhiro, Takuwa Noriko, Takuwa Yoh
  • Organizer: 第 95 回日本生理学会大会
• [Presentation] Class II phosphoinositide 3-kinase isoforms PI3K-C2αand PI3K-C2β play essential roles in pinocytosis in vascular endothelial cells (2018)
  • Author(s): Aung Thuzar Khin, Yoshioka Kazuaki, Aki Sho, Pham Quynh Hoa, Sarker Kabir Azadul, Islam Shahidul, Ishimaru Kazuhiro, Takuwa Noriko, Takuwa Yoh
  • Organizer: 第 95 回日本生理学会大会
• [Presentation] Novel indispensable role of and isoforms of class II PI3K for uterine smooth muscle contraction and labor (2018)
  • Author(s): Azadul Kabir Sarker, Sho Aki, Kazuaki Yoshioka, Koji Kuno, Kazuhiro Ishimaru, Noriko Takuwa, Yoh Takuwa
  • Organizer: 第54回北陸生殖医学会学術講演会
• [Presentation] S1P2によるブレオマイシン誘発肺線維症の増悪機構の検討:肺胞マクロファージの細胞老化制御の関与 (2018)
  • Author(s): 多久和典子, 岡本安雄, 石丸和宏, 多久和陽
  • Organizer: 日本病態生理学会
• [Presentation] Sphingosine Kinase 2 Inhibits Macrophage Cholesterol Accumulation and Atherosclerosis via Autophagy Stimulation (2018)
  • Author(s): Kazuhiro Ishimaru, Yoh Takuwa
  • Organizer: American Heart Association 2018 Scientific Sessions
  • Int'l Joint Research
• [Presentation] Myotubularin-related protein 4 (MTMR4), a phosphoinositide 3'-phosphatase, regulates endolysosome integrity and autophagy flux in human lung alveolar epithelial A549 cells (2018)
  • Author(s): Pham Quynh Hoa, Yoshioka Kazuaki, Azadul Sarker Kabir, Aung Thuzar Khin, Islam Shahidul, Aki Sho, Ishimaru Kazuhiro, Takuwa Noriko, Takuwa Yoh
  • Organizer: 第95回日本生理学会大会
• [Presentation] Class II phosphoinositide 3-kinase isoforms PI3K-C2α and PI3K-C2β play essential roles in pinocytosis in vascular endothelial cells (2018)
  • Author(s): Aung Thuzar Khin, Yoshioka Kazuaki, Aki Sho, Pham Quynh Hoa, Sarker Kabir Azadul, Islam Shahidul, Ishimaru Kazuhiro, Takuwa Noriko, Takuwa Yoh
  • Organizer: 第95回日本生理学会大会
• [Presentation] 抗がん剤による臓器障害におけるスフィンゴシン-1-リン酸（S1P）情報伝達系の関与 (2017)
  • Author(s): 多久和 典子、石丸 和宏、岡本 安雄、多久和 陽
  • Organizer: 第27回日本病態生理学会大会