How angiogenesis is regulated by pharmacological intervention of the intracellular cholinergic system?

2008 Fiscal Year Final Research Report

• Project/Area Number: 19590251
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Kochi University
• Principal Investigator: KAKINUMA Yoshihiko Kochi University, 教育研究部・医療学系, 准教授 (60265866)
• Co-Investigator(Renkei-kenkyūsha): SATO Takayuki 高知大学, 教育研究部・医療学系, 教授 (90205930) ; ARIKAWA Mikihiko 高知大学, 教育研究部・医療学系, 助教 (20432817)
• Project Period (FY): 2007 – 2008
• Keywords: 循環

Research Abstract

アセチルコリン(ACh)には、血管内皮細胞に対してムスカリン受容体およびニコチン容体の両者を通して、血管新生に関わるシグナル伝達系、たとえばPI3K/Akt系の活性化、その後の非低酸素下でのHIF-1αの蛋白レベルの上昇、VEGFの発現誘導、結果としてin vitroでの血管新生促進作用が存在することを証明した。この効果をacetylcholinesterase inhibitorであるdonepezilを用いて、マウス下肢虚血モデルを用いて検討した。Donepezilの投与量を低量(ヒトの場合と同程度)と高容量で比較しても、両者において血管新生促進作用が認められた。いずれも、虚血による下肢筋肉萎縮を抑制し、下肢血液還流を保持し、結果として皮膚温の低下も抑制した。病理学的には、donepezilにより毛細血管の密度が増加し、VEGF陽性の血管内皮細胞の数も顕著に増加した。Donepezilの詳細な作用機序については、acetylcholinesterase inhibitorとしての作用と、inhibitor以外のものとが考えられた。

Research Products

• [Journal Article] Donepezilを使用した容量負荷心不全マウスにおける心機能改善効果、生存率改善効果の検討 (2009)
  • Author(s): 半田武巳、Katare GR、柿沼由彦, 有川幹彦、安藤元規、山崎文靖、佐藤隆幸、篠栗志朗
  • Journal Title: 心臓 41(2) Pages: 115-123
• [Journal Article] Chronic intermittent fasting improves the survival following large myocardial ischemia by activation of BDNF/VEGF/PI3K signaling pathway (2009)
  • Author(s): Katare GR, Kakinuma Y, Arikawa M, Yamasaki F, Sato T.
  • Journal Title: J Mol Cel Cardiol 46 Pages: 405-412
• [Journal Article] Vagal nerve stimulation prevents reperfusion injury through inhibition of opening of mitochondrial permeability transition pore independent of the bradycardiac effect (2009)
  • Author(s): Katare GR, Ando M, Kakinuma Y, Arikawa M, Handa T, Yamasaki F, Sato T
  • Journal Title: J Thorac Cardiovasc Surgery 137 Pages: 223-231
• [Journal Article] Acute Inactivation of the VHL gene Contributes to Protective Effects of Ischemic Preconditioning in the Mouse Kidney (2008)
  • Author(s): Iguchi M, Kakinuma Y, Kurabayashi A, Sato T, Shuin T, Hong S-B, Schmidt LS, Furihata M
  • Journal Title: Nephron, Nephron Exp Nephrol 110 Pages: e82-e90
  • Peer Reviewed
• [Journal Article] A HIF-1alpha-related gene involved in cell protection from hypoxia by suppression of mitochondrial function (2008)
  • Author(s): Kakinuma Y, Katare RG, Arikawa M, Muramoto K, Yamasaki F, Sato T
  • Journal Title: FEBS Lett 582 Pages: 332-340
  • Peer Reviewed
• [Presentation] Donepezil, an Acetylcholinesterase Inhibitor Against Alzheimers Dementia, Prevents Remodeling in Volume-Overload Heart Failure Mice : Local and Central effect of Donepezil (2009)
  • Author(s): Handa T, Sato T, Kakinuma Y, Arikawa M, Sasaguri S
  • Organizer: 第73回日本循環器学会学術総会
  • Place of Presentation: 大阪
  • Year and Date: 20090320-22
• [Presentation] Cardiomyocytes Produces Acetylcholine in Circulation Response to Muscarinic Receptor Stimulation : a Possible Mechanism for Amplification of Cardioprotective Effects of Cardiac Vagal Nerve Circulation 116 : II-159(819) (2008)
  • Author(s): Kakinuma Y, Akiyama T, Arikawa M, Handa T, Sato T.
  • Organizer: Scientific Session 2008 American Heart Association
  • Place of Presentation: New Orleans, Louisiana, USA
  • Year and Date: 20081108-12
• [Presentation] Donepezil, Anti-Alzheimer's Disease Drug, Prevented the Progression of Ventricular Dysfunction after Myocardial Infarction (2008)
  • Author(s): Arikawa M, Katare R, Kakinuma Y, Handa T, Andoh M,Yamasaki F, Sato T
  • Organizer: 第72回日本循環器学会学術総会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 20080328-30
• [Presentation] Donepezil, an Acetylcholinesterase Inhibitor Against Alzheimers Dementia, Prevents Remodeling and Improves Survival in Volume-Overload Heart Failure Mice (2008)
  • Author(s): Handa T, Sato T, Kakinuma Y, Arikawa M.
  • Organizer: 第72回日本循環器学会学術総会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 20080328-30
• [Presentation] A HIF-1α-related gene involved in cell protection from hypoxia by suppression of mitochondrial function (2008)
  • Author(s): Kakinuma Y, Sato T.
  • Organizer: 第9回 Neurocardiology Workshop
  • Place of Presentation: 東京ステーションコンファレンス
  • Year and Date: 2008-07-26
• [Presentation] Acetylcholiesterase Inhibitor Against Alzheimer's Dementia, Promotes Angiogenesis in an Ischemic Limb Model of Nicotinic α7 KO Mice Circulation 116 : II-159(819) (2007)
  • Author(s): Kakinuma Y, Katare GR, Arikawa M, Handa T, Yamasaki F, Li M, Zheng C, Sugimachi M, Sato T.
  • Organizer: Scientific Session 2007 American Heart Association
  • Place of Presentation: Orland, Florida, USA
  • Year and Date: 20071104-07
• [Presentation] Myocardial Infarction is Prevented by Anti-Alzheimer's Disease Drug, Donepezil Circulation 116 : II-291(1416) (2007)
  • Author(s): 7.Arikawa M, Katare GR, Kakinuma Y, Handa T, Ando M, Yamasaki F, Sato T.
  • Organizer: Scientific Session 2007 American Heart Association
  • Place of Presentation: Orland, Florida, USA
  • Year and Date: 20071104-07
• [Presentation] Tumor Necrosis Factor Receptor-2 Plays a Critical Role for Induction of Post Ischemic Neovascularization in Mouse Model of Hind Limb Ischemia. Circulation 116 : II-274(1339) (2007)
  • Author(s): Katare GR., Kakinuma Y, Arikawa M, Handa T, Yamasaki F, Sato T.
  • Organizer: Scientific Session 2007 American Heart Association
  • Place of Presentation: Orland, Florida, USA
  • Year and Date: 20071104-07
• [Presentation] Nitric Oxide Has Beneficial Effects on Cardiomyocytes by Activation of the Vascular Endothelial Growth Factor (2007)
  • Author(s): Kuwabara M, Kakinuma Y, Andoh M, Katare R, Yamasaki F, Doi Y, Sato T.
  • Organizer: 第71回日本循環器学会学術総会
  • Place of Presentation: 神戸コンベンションセンター
  • Year and Date: 20070315-17
• [Presentation] Cholinesterase Inhibitor Donepezil Improves Ventricular Function of Mice with Non-Ischemic Chronic Heart Failure (2007)
  • Author(s): Handa T, Katare R, Kakinuma Y, Arikawa M, Ando M, Sasaguri S, Sato T.
  • Organizer: 第71回日本循環器学会学術総会
  • Place of Presentation: 神戸コンベンションセンター
  • Year and Date: 20070315-17
• [Presentation] Donepezil Promotes Angiogenesis through the Mechanisms Independent of Cholinesterase Inhibition and Nicotinic α7 Receptor (2007)
  • Author(s): Kakinuma Y, Katare R, Arikawa M, Handa T, Andoh M, Li M, Zheng C, Yamasaki F, Sato T.
  • Organizer: 第71回日本循環器学会学術総会
  • Place of Presentation: 神戸コンベンションセンター
  • Year and Date: 20070315-17
• [Presentation] Cardiomyocytes Produce Acetylcholine in Response to Muscarinic Receptor Agonists : a Possible Mechanism for Cardioprotective Effects of Vagal Stimulation on Cardiomyocytes (2007)
  • Author(s): Kakinuma Y, Katare R, Arikawa M, Handa T, Akiyama T, Andoh M, Yamasaki F, Sato T
  • Organizer: 第71回日本循環器学会学術総会
  • Place of Presentation: 神戸コンベンションセンター
  • Year and Date: 20070315-17
• [Presentation] Vagal Nerve Stimulation Protects Heart Against Ischemic Insult through Differential Regulation of Myocardial TNF Receptor Subtypes (2007)
  • Author(s): Katare R, Andoh M, Kakinuma Y, Arikawa M, Handa T, Yamasaki F, Sato T
  • Organizer: 第71回日本循環器学会学術総会
  • Place of Presentation: 神戸コンベンションセンター
  • Year and Date: 20070315-17
• [Presentation] Vagal Nerve Stimulation Salvage the Myocardium Agaisnt Reperfusion Injury Through Inhibition of Opening of Mitochondrial Permeability Transition Pore (2007)
  • Author(s): Katare R, Kakinuma Y, Andoh M, Arikawa M, Handa T, Sasaguri S, Yamasaki F, Sato T.
  • Organizer: 第71回日本循環器学会学術総会
  • Place of Presentation: 神戸コンベンションセンター
  • Year and Date: 20070315-17
• [Presentation] Electrophysiological Approaches to the Mechanism of Arrhythmogenesis in Artificially-Arranged Cardiomyocytes (2007)
  • Author(s): Arikawa M, Katare R, Kakinuma Y, Andoh M, Handa T, Yamasaki F, Sato T.
  • Organizer: 第71回日本循環器学会学術総会
  • Place of Presentation: 神戸コンベンションセンター
  • Year and Date: 20070315-17
• [Presentation] Donepezil Promotes Angiogenesis in an Ischemic Limb Model of Nicotinic α7 Receptor KO Mice (2007)
  • Author(s): Kakinuma Y, Katare GR, Arikawa M, Handa T, Yamsaki F, Sato T.
  • Organizer: 第8回Neurocardiology Workshop
  • Place of Presentation: 経団連会館
  • Year and Date: 2007-07-21