Base construction for the development of therapeutic strategies for targeting cell adhesion molecules in atherosclerosis

• Project/Area Number: 25461128
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Kobe Pharmaceutical University (2015); Kobe University (2013-2014)
• Principal Investigator: Rikitake Yoshiyuki 神戸薬科大学, 薬学部, 教授 (50419488)
• 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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 細胞接着分子 / 血管内皮細胞 / シグナル伝達 / 内膜肥厚 / 血管炎症 / 糖鎖修飾 / 接触阻害 / 炎症 / 血管平滑筋細胞 / 運動 / 増殖

Outline of Final Research Achievements

The following findings were obtained by analyzing the functions and mode of action of cell adhesion molecules in atherosclerosis. (1) Necl-5 facilitated dedifferentiation of smooth muscle cells from a contractile to a synthetic phenotype, cell movement and proliferation, and intimal thickening after the common carotid artery ligation. (2) Necl-4, whose expression increased as vascular endothelial cells become confluent, induced contact inhibition of movement and proliferation by suppressing autophosphorylation of the vascular endothelial growth factor receptor via PTPN13. (3) In vascular endothelial cells FAM5C increased in response to inflammatory stimuli and promoted expression of monocyte adhesion molecules via enhanced production of reactive oxygen species and activation of NF-kappa B.

Research Products

• [Journal Article] The cell adhesion molecule necl-4/cadm4 serves as a nobel regulator for contact inhibition of cell movement and proliferation. (2015)
  • Author(s): Yamana S, Tokiyama A, Mizutani K, Hirata K, Takai Y, Rikitake Y.
  • Journal Title: PloS One. Volume: 10 Issue: 4 Pages: e0124259-e0124259
  • DOI: 10.1371/journal.pone.0124259
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of Rho-associated protein kinase (ROCK) and bone morphogenetic protein-binding endothelial cell precursor-derived regulator (BMPER) in high glucose-increased alkaline phosphatase expression and activity in human coronary artery smooth muscle cells. (2015)
  • Author(s): Terao Y, Satomi-Kobayashi S, Hirata K, Rikitake Y.
  • Journal Title: Cardiovasc Diabetol. Volume: 14 Issue: 1 Pages: 104-104
  • DOI: 10.1186/s12933-015-0271-7
  • NAID: 120005650141
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Family with sequence similarity 5, member C (FAM5C) increases leukocyte adhesion molecules in vascular endothelial cells: Implication in vascular inflammation. (2014)
  • Author(s): Sato J, Kinugasa M, Satomi-Kobayashi S, Hatakeyama K, Knox AJ, Asada Y, Wierman ME, Hirata K, Rikitake Y.
  • Journal Title: PLoS ONE. Volume: 9 Issue: 9 Pages: e107236-e107236
  • DOI: 10.1371/journal.pone.0107236
  • NAID: 120005549604
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Nectin-like molecule-5 regulates intimal thickening after carotid artery ligation in mice. (2013)
  • Author(s): Kureha F, Satomi-Kobayashi S, Kubo Y, Kinugasa M, Ishida T, Takai Y, Hirata K, Rikitake Y.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 33 Issue: 6 Pages: 1206-1211
  • DOI: 10.1161/atvbaha.113.301425
  • Peer Reviewed / Open Access
• [Presentation] 血管平滑筋細胞における高グルコース誘導性のアルカリフォスファターゼ（ALP）遺伝子発現増加およびALP活性亢進へのRho-ROCK経路およびBMPERの関与 (2015)
  • Author(s): 寺尾 侑也、小林 成美、平田 健一、力武 良行
  • Organizer: 第23回日本血管生物医学会学術集会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-11
• [Presentation] Regulation of Angiogenesis by the Immunoglobulin-like Molecule Necl-5 (2015)
  • Author(s): Yoshiyuki Rikitake
  • Organizer: BMB2015（第38回日本分子生物学会年会・第88回日本生化学会大会 合同大会）
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-04
  • Invited
• [Presentation] ArhGAP29, a RhoGAP, Interacts with Afadin in the Regulation of ROCK Activity, Network Formation and Migration of Endothelial Cell (2015)
  • Author(s): Toru Tagashira, Muneaki Miyata, Terunobu Fukuda, Shota Yamana, Ken-ichi Hirata, Yoshiyuki Rikitake
  • Organizer: 第79回日本循環器学会総会・学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2015-04-25
• [Presentation] A Dual Role of Cell Adhesion Molecule Necl-4 in Endothelial Cells: Promotion of Migration Under Sparse Conditions and Inhibition of Proliferation Under Confluent Conditions (2014)
  • Author(s): Shota Yamana, Amina Tokiyama, Yuya Terao, Ken-ichi Hirata, Yoshiyuki Rikitake
  • Organizer: Scientific Sessions 2014, American Heart Association
  • Place of Presentation: Chicago, USA
  • Year and Date: 2014-11-17
• [Presentation] Nectin and heterotypic cell－cell adhesion (2014)
  • Author(s): Yoshiyuki Rikitake
  • Organizer: the 2014 Annual Meeting of Korean Society for Biochemistry and Molecular Biology
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2014-05-14
  • Invited
• [Presentation] Regulation of Network Formation and Migration of Vascular Endothelial Cells by Necl-4 through the PTPN13-ROCK Pathway (2014)
  • Author(s): Shota Yamana, Amina Tokiyama, Mitsuo Kinugasa, Yuya Terao, Yoshimi Takai, Ken-ichi Hirata, Yoshiyuki Rikitake
  • Organizer: IVBM2014. The 18th International Vascular Biology Meeting
  • Place of Presentation: 京都
  • Year and Date: 2014-04-14 – 2014-04-17
• [Presentation] Necl-4による血管内皮細胞の運動と管腔形成の制御
  • Author(s): 山名祥太、力武良行、高井義美、平田健一
  • Organizer: 第21回日本血管生物医学会学術集会
  • Place of Presentation: 千里ライフサイエンスセンター
• [Presentation] 山名祥太、力武良行、高井義美、平田健一
  • Author(s): Necl-4による血管内皮細胞の運動と管腔形成の制御
  • Organizer: 第43 回日本心脈管作動物質学会
  • Place of Presentation: 神戸国際会議場
• [Presentation] Regulation of Vascular Endothelial Cell Functions by Necl-4 through the PTPN13-ROCK Pathway
  • Author(s): Shota Yamana, Mitsuo Kinugasa, Yuya Terao, Ken-ichi Hirata, Yoshiyuki Rikitake
  • Organizer: 第78回日本循環器学会総会・学術集会
  • Place of Presentation: 東京国際フォーラム
• [Presentation] Expression and pro-inflammatory functions of FAM5C, a genetic risk factor for acute mayocardial infarction, in vascular endothelial cells
  • Author(s): Mitsuo Kinugasa, Yoshiyuki Rikitake, Seimi Satomi-Kobayashi, Kinta Hatakeyama, Shota Yamana, Fumie Kureha, Junya Satoh, Yujiro Asada, Ken-ichi Hirata
  • Organizer: 第78回日本循環器学会総会・学術集会
  • Place of Presentation: 東京国際フォーラム
• [Remarks] 神戸大学大学院医学研究科シグナル伝達学分野ホームページ
  • URL: http://www.med.kobe-u.ac.jp/sigtra/Signal_Transduction/Home.html
• [Remarks] 神戸大学大学院医学研究科シグナル伝達学分野ホームページ
  • URL: http://www.med.kobe-u.ac.jp/sigtra/Signal_Transduction/Home.html