Mechanisms of impaired EDHF during hypertension.

• Project/Area Number: 16K09645
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Kyushu University
• Principal Investigator: Goto Kenichi 九州大学, 大学病院, 講師 (30549887)
• Research Collaborator: Seki Takunori ; Noguchi Hideko ; Ohtsubo Toshio
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 血管内皮機能 / 高血圧 / 内皮依存性過分極 / TRPV4チャネル / カルシウム感受性カリウムチャネル / ラット / 内皮由来過分極 / KCaチャネル / 高血圧ラット / カルシウム活性化カリウムチャネル / 血管内皮機能障害 / ＴＲＰＶ４チャネル / 循環器・高血圧

Outline of Final Research Achievements

The results of the present study demonstrated that: (1) functional TRPV4 is expressed in endothelial cells of rat mesenteric arteries; (2) the opening of endothelial TRPV4 channels and the downstream activation of SKCa and IKCa are involved in ACh-induced, EDH-mediated responses in this vascular bed; (3) endothelial TRPV4 and SKCa channels are downregulated in genetically hypertensive rats but not in normotensive rats, contributing to the impaired EDH-mediated responses in mesenteric arteries of genetically hypertensive rats.

Academic Significance and Societal Importance of the Research Achievements

高血圧において内皮依存性弛緩反応は障害されており、内皮機能障害は高血圧患者における心血管疾患の発症と関連している。したがって、高血圧における内皮機能障害の機序を解明すること、内皮機能障害の有効な治療法を開発することは臨床的にも重要である。本研究により、遺伝性高血圧ラットにおける内皮依存性過分極反応の障害が、血管内皮細胞におけるTRPV4とSKCaチャネルの発現低下に起因することが明らかとなった。今後、高血圧患者において、TRPV4とSKCaチャネルを標的とした心血管疾患の新たな予防法や治療法の開発に繋がることが期待される。

Research Products

• [Journal Article] Endothelium-dependent hyperpolarization (EDH) in hypertension: The role of endothelial ion channels. (2018)
  • Author(s): Goto Kenichi; Ohtsubo Toshio; Kitazono Takanari
  • Journal Title: International Journal of Molecular Sciences Volume: 19 Issue: 1 Pages: 315-315
  • DOI: 10.3390/ijms19010315
  • Peer Reviewed / Open Access
• [Journal Article] Downregulation of endothelial transient receptor potential vanilloid type 4 channel and small-conductance of Ca2+-activated K+ channels underpins impaired endothelium-dependent hyperpolarization in hypertension. (2017)
  • Author(s): Seki, Takunori; Goto, Kenichi; Kiyohara, Kanako; Kansui, Yasuo; Murakami, Noboru; Haga, Yoshie; Ohtsubo, Toshio; Matsumura, Kiyoshi; Kitazono, Takanari
  • Journal Title: Hypertension Volume: ６９ Issue: 1 Pages: 143-153
  • DOI: 10.1161/hypertensionaha.116.07110
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Downregulation of endothelial transient receptor potential vanilloid type 4 channel and small-conductance of Ca2+-activated K+ channels underpins impaired endothelium-dependent hyperpolarization in hypertension (2017)
  • Author(s): Seki Takunori; Goto Kenichi; Kiyohara Kanako; Kansui Yasuo; Murakami Noboru; Haga Yoshie; Ohtsubo Toshio; Matsumura Kiyoshi; Kitazono Takanari
  • Organizer: 第40回日本高血圧学会総会
• [Presentation] Downregulation of endothelial TRPV4 channel contributes to the reduced endothelium-dependent hyperpolarization in genetically hypertensive rats. (2016)
  • Author(s): Seki, Takunori; Goto, Kenichi; Kiyohara, Kanako; Kansui, Yasuo; Murakami, Noboru; Haga, Yoshie; Ohtsubo, Toshio; Matsumura, Kiyoshi; Kitazono, Takanari
  • Organizer: The 26th Meeting of the International Society of Hypertension
  • Place of Presentation: Coex, Seoul, Korea
  • Year and Date: 2016-09-24
  • Int'l Joint Research