The role of prostaglandin F2 alpha in the regulation of platelet function

• Project/Area Number: 26860167
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General pharmacology
• Research Institution: Asahikawa Medical College
• Principal Investigator: KASHIWAGI Hitoshi 旭川医科大学, 医学部, 助教 (60510609)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2016: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2015: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: 血小板 / プロスタグランジンF2α / EP3受容体 / TP受容体 / 受容体欠損マウス

Outline of Final Research Achievements

In murine platelets, PGF2α potentiated adenosine diphosphate-induced platelet aggregation in a concentration-dependent manner, while PGF2α alone did not induce aggregation. In platelets lacking PGF2α receptor FP, however, PGF2α-induced potentiation was not significantly different from that in wild-type (WT) platelets. In contrast, the potentiation was significantly blunted in platelets lacking PGE2 receptor subtype EP3 or TXA2 receptor TP, and completely disappeared in platelets lacking both EP3 and TP. In vivo, intravenously administered PGF2α shortened the bleeding time in WT mice. Moreover, PGF2α increased mortality and thrombus formation in arachidonic acid-induced thromboembolism model.
In conclusion, PGF2α potentiates platelet aggregation via EP3 and TP, but not via FP, and the potentiating action may play important role under physiological and pathological conditions.

Research Products

• [Journal Article] The novel prostaglandin I2 mimetic ONO-1301 escapes desensitization in an anti-platelet effect due to its inhibitory action on thromboxane A2 synthesis in mice (2015)
  • Author(s): Hitoshi Kashiwagi, Koh-ichi Yuhki, Fumiaki Kojima, Shima Kumei, Osamu Takahata, Yoshiki Sakai, Shuh Narumiya and Fumitaka Ushikubi
  • Journal Title: The Journal of pharmacology and experimental therapeutics Volume: 353 Issue: 2 Pages: 269-278
  • DOI: 10.1124/jpet.115.222612
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 臓器線維化におけるプロスタノイドの役割 (2015)
  • Author(s): 結城幸一、柏木仁、小島史章、今道力敬、牛首文隆
  • Journal Title: 細胞 Volume: 47 Pages: 16-19
• [Journal Article] 虚血による神経障害の分子メカニズム プロスタノイドの役割 (2014)
  • Author(s): 小島史章、結城幸一、柏木仁、粂井志麻、牛首文隆
  • Journal Title: 日本臨牀 Volume: 72 Pages: 121-125
• [Presentation] Prostaglandin F2α potentiates platelet aggregation via prostaglandin E2 and thromboxane A2 receptors (2017)
  • Author(s): Hitoshi Kashiwagi, Koh-ichi Yuhki, Yoshitaka Imamichi, Fumiaki Kojima, Shima Kumei, Shuh Narumiya, Fumitaka Ushikubi
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホール（長崎県長崎市）
  • Year and Date: 2017-03-15
• [Presentation] プロスタグランジンF2αの血小板凝集促進作用 (2016)
  • Author(s): 柏木仁、結城幸一、今道力敬、小島史章、粂井志麻、成宮周、牛首文隆
  • Organizer: 第26回日本循環薬理学会
  • Place of Presentation: 信州大学医学部付属病院（長野県松本市）
  • Year and Date: 2016-12-02
• [Presentation] Promoting effect of prostaglandin F2α on platelet aggregation (2016)
  • Author(s): Hitoshi Kashiwagi, Koh-ichi Yuhki, Yoshitaka Imamichi, Fumiaki Kojima, Shima Kumei, Shuh Narumiya, Fumitaka Ushikubi
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜（横浜市、神奈川県）
  • Year and Date: 2016-03-09
• [Presentation] 血小板機能調節におけるプロスタノイドの役割 (2015)
  • Author(s): 柏木仁
  • Organizer: 第17回旭川心血管リモデリング研究会
  • Place of Presentation: 旭川グランドホテル（旭川市、北海道）
  • Year and Date: 2015-11-20
  • Invited
• [Presentation] タバコ煙抽出液は血小板凝集を抑制する (2015)
  • Author(s): 柏木仁、結城幸一、今道力敬、小島史章、粂井志麻、成宮周、牛首文隆
  • Organizer: 第66回日本薬理学会北部会
  • Place of Presentation: 富山国際会議場（富山市、富山県）
  • Year and Date: 2015-09-18
• [Presentation] ヒト生殖腺における11-ケトテストステロンの合成とその機能 (2015)
  • Author(s): 今道力敬、矢澤隆志、結城幸一、柏木仁、宮本薫、牛首文隆
  • Organizer: 第66回日本薬理学会北部会
  • Place of Presentation: 富山国際会議場（富山市、富山県）
  • Year and Date: 2015-09-18
• [Presentation] Protective effects of the prostaglandin I2-IP signal in nonalcoholic steatohepatitis (2015)
  • Author(s): Shima Kumei, Koh-ichi Yuhki, Hitoshi Kashiwagi, Toshikatsu Okumura, Fumitaka Ushikubi
  • Organizer: Digestive Disease Week (DDW) 2015
  • Place of Presentation: Walter E. Washington Convention Center (Washington, D.C., USA)
  • Year and Date: 2015-05-16
  • Int'l Joint Research
• [Presentation] Cigarette smoke extract inhibits platelet aggregation (2015)
  • Author(s): Hitoshi Kashiwagi, Koh-ichi Yuhki, Fumiaki Kojima, Shima Kumei, Shuh Narumiya, Fumitaka Ushikubi
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] Roles of the prostaglandin I2-IP system in nonalcoholic steatohepatitis (2015)
  • Author(s): Shima Kumei, Koh-ichi Yuhki, Fumiaki Kojima, Hitoshi Kashiwagi, Toshikatsu Okumura, Shuh Narumiya, Fumitaka Ushikubi
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] 血小板凝集に及ぼすタバコ煙抽出液の作用 (2014)
  • Author(s): 柏木仁、結城幸一、小島史章、粂井志麻、成宮周、牛首文隆
  • Organizer: 第24回日本循環薬理学会
  • Place of Presentation: 山形テルサ（山形県・山形市）
  • Year and Date: 2014-12-05
• [Presentation] タバコ煙抽出液の血小板凝集抑制作用 (2014)
  • Author(s): 柏木仁、結城幸一、小島史章、粂井志麻、牛首文隆
  • Organizer: 第65回日本薬理学会北部会
  • Place of Presentation: コラッセ福島（福島県・福島市）
  • Year and Date: 2014-09-26 – 2014-09-27
• [Presentation] 非アルコール性脂肪性肝炎におけるプロスタノイドの役割解明 (2014)
  • Author(s): 結城幸一、粂井志麻、柏木仁、小島史章、成宮周、牛首文隆
  • Organizer: 第65回日本薬理学会北部会
  • Place of Presentation: コラッセ福島（福島県・福島市）
  • Year and Date: 2014-09-26 – 2014-09-27
• [Presentation] Protective effect of the prostaglandin I2-IP signal through the suppression of cytokines expression in nonalcoholic steatohepatitis (2014)
  • Author(s): Shima Kumei, Koh-ichi Yuhki, Fumiaki Kojima, Hitoshi Kashiwagi, Toshikatsu Okumura, Fumitaka Ushikubi
  • Organizer: Digestive Disease Week (DDW) 2014
  • Place of Presentation: Chicago（USA）
  • Year and Date: 2014-05-03 – 2014-05-06