Estimation of coupling factor 6-induced vascular damage and utilization for drug discovery

2011 Fiscal Year Final Research Report

• Project/Area Number: 21590946
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Hirosaki University
• Principal Investigator: OSANAI Tomohiro 弘前大学, 大学院・医学研究科, 准教授 (00169278)
• Co-Investigator(Kenkyū-buntansha): OKUMURA Ken 弘前大学, 大学院・医学研究科, 教授 (20185549)
• Project Period (FY): 2009 – 2011
• Keywords: Coupling factor 6 / Angiotensin II / Vascular smooth muscle cells / Mesenteric arteriole / Spontaneously hypertensive rat

Research Abstract

Coupling factor 6 (CF6) bound to ss-sunbunit of ATP synthase at the surface of vascular smooth muscle cells (VSMC), and induced proton influx into the cytoplasm via degradation of ATP to ADP. CF6 induced influx of extracellular calcium and increased intracellular free calcium concentration in response to angiotensin II. These responsiveness of calcium to CF6 was enhanced in spontaneously hypertensive rats (SHR) compared with Wister Kyoto rats, and were abolished after pretreatment with anti-CF6-C terminus antibody, suggesting that the C-terminus of CF6 is involved in the action of its peptide. In the experiment of mesenteric arteries, CF6 in the arteriole induced the contraction in response to angiotensin II via activation of tyrosine kinase c-Src, and it was attenuated by pretreatment with anti-CF6-C terminus antibody. Overall, these suggest that inhibition of CF6 may antagonize the action of angiotensin II as other inhibitors of rennin-angiotensin system.

Research Products

• [Journal Article] Novel pro-atherogenic molecule coupling factor 6 is elevated in patients with stroke : A possible linkage to homocysteine (2010)
  • Author(s): Osanai T, Fujiwara N, Sasaki S, Metoki N, Saitoh G, Tomita H, Nishimura T, Shibitani S, Yokoyama H, Konta Y, Magota K, Okumura K
  • Journal Title: Ann Med Volume: 42 Pages: 79-86
• [Journal Article] Overexpression of coupling factor 6 causes cardiac dysfunction under high salt diet in mice (2010)
  • Author(s): Ashitate T, Osanai T, Tanaka M, Magota K, Echizen T, Izumiyama K, Yokoyama H, Shibutani S, Hanada K, Tomita H, Okumura K
  • Journal Title: J Hypertens Volume: 28 Pages: 2243-2251
• [Journal Article] Coupling factor 6 enhances Src-mediated responsiveness to angiotensin II in resistance arterioles and cells (2009)
  • Author(s): Osanai T, Tomita H, Kushibiki M, Yamada M, Tanaka M, Ashitate T, Echizen T, Katoh C, Magota K, Okumura K
  • Journal Title: Cardiovasc Res Volume: 81 Pages: 780-787
• [Journal Article] Coupling factor 6-induced prostacyclin inhibition is enhanced in vascular smooth muscle cells from spontaneously hypertensive rats (2009)
  • Author(s): Osanai T, Tomita H, Yamada M, Tanaka M, Ashidate T, Echizen T, Katoh C, Magota K, Okumura K
  • Journal Title: J Hypertens Volume: 27 Pages: 1823-1828
• [Journal Article] Coupling factor 6 as a novel vasoactive and proatherogenic peptide in vascular endothelial cells (2009)
  • Author(s): Osanai T, Magota K, Okumura K
  • Journal Title: Naunyn Schmiedebergs Arch Pharmacol Volume: 380 Pages: 205-214
• [Presentation] Coupling factor 6 induces tissue acidosis and thereby salt-sensitive hypertension with diabetes by Rac1 activation and insulin receptor inactivation (2011)
  • Author(s): Osanai T, Okumura K
  • Organizer: Scientific Sessions 2011 (American Heart Association)
  • Place of Presentation: Orland (USA)
  • Year and Date: 20111113-16
• [Presentation] Coupling factor 6は細胞内酸性化を介してRac1を活性化し食塩感受性高血圧とインスリン抵抗性を惹起する (2011)
  • Author(s): 長内智宏、泉山圭、相楽繁樹、山本祐子、奥村謙
  • Organizer: 第34回日本高血圧学会総会
  • Place of Presentation: 宇都宮
  • Year and Date: 20111020-22
• [Presentation] Interaction between coupling factor 6 and ecto F1Fo complex induces hypertension and diabetes by tissue acidosis (2010)
  • Author(s): Osanai T, Okumura K
  • Organizer: Scientific Sessions 2010 (American Heart Association)
  • Place of Presentation: Chicago (USA)
  • Year and Date: 20101114-17
• [Presentation] 新規の細胞内pH調節機構F_1F_o complexはcoupling factor 6で活性化され血圧並びに糖代謝を調節する (2010)
  • Author(s): 長内智宏、渋谷修司、花田賢二、泉山圭、相楽繁樹、山本祐子、奥村謙
  • Organizer: 第33回日本高血圧学会総会
  • Place of Presentation: 福岡
  • Year and Date: 20101015-17
• [Presentation] Coupling factor 6 enhances the action of angiotensin II and causes insulin resistance in mice (2009)
  • Author(s): Osanai T, Okumura K
  • Organizer: Scientific Sessions 2009 (American Heart Association)
  • Place of Presentation: Orland (USA)
  • Year and Date: 20091115-18
• [Presentation] 新規の昇圧物質coupling factor 6 はcSrcの活性化を介してangiotensin IIの収縮反応を亢進させる (2009)
  • Author(s): 長内智宏、櫛引基、山田雅大、奥村謙
  • Organizer: 第32回日本高血圧学会総会
  • Year and Date: 20091001-03