細胞老化制御による進行動脈硬化症治療―本邦高齢者へのオーダーメイド治療を目指す―

2009 Fiscal Year Annual Research Report

• Project/Area Number: 21590762
• Research Institution: Nagoya University
• Principal Investigator: 林 登志雄 Nagoya University, 医学部付属病院, 講師 (80303634)
• Co-Investigator(Kenkyū-buntansha): 梅垣 宏行 名古屋大学, 医学部附属病院, 助教 (40345898)
• Keywords: 一酸化窒素 / 動脈硬化症 / 細胞老化 / エストロゲン / 糖尿病 / 動脈硬化退縮 / 血管内皮細胞

Research Abstract

高齢者動脈硬化症の特徴に基づいた細胞老化制御療法の有効性の明らかな手法の確立を目標とした。危険因子として加齢及び高齢者に普遍的な高脂血症と糖尿病の合併を想定、細胞老化をtelomerase, NO及び活性酸素制御等により制御し血管壁構成細胞での動脈硬化進展抑制効果を検討した。特許申請中の方法を含むNO bioavailability増加療法との関連も調べた。#1NO,活性酸素関遺伝子ベクター調整:eNOS, iNOS vectorに加え、eNOSsiRNA, NADPHoxidase(p47phox)siRNA vectorを作成した。
#2遺伝子導入による老化制御及び各種内皮機能の検討各種老化指標(テロメラーゼ活性,テロメア長、老化関連βガラクトシダーゼ染色性等)NO放出能(酵素活性、NO代謝物、eNOSmRNA,同蛋白),活性酸素放出能(MLCA, FACScan)の基礎検討を行った。
#3遺伝子導入時の補酵素、阻害剤等の組み合わせ利用NO産生増加,NOS uncoupling及びNADPH oxidase活性化等によるO_2^<->産生制御を目標とし条件を検討した。L-argnine, L-citrulline(citrulline-arginine回路),BH4等のNO合成酵素基質及び補酵素,L-NAME, apocynin等の阻害酵素を用いた。血管内皮にしぼり検討した。NO及びエストロゲンは上記テロメラーゼ活性を増加させ、replicative senescemceを制御した。
#4病態(細胞レベル)での検討:高脂血症、糖尿病モデルでの老化制御作用を検討した。本年は血管内皮細胞に限った。糖尿病では従来3日間の高グルコース負荷を中心にデータを蓄積してきたが、7日以上の長期負荷及び,1日2、3回の食後高血糖モデルも確立し、成績を得た。

Research Products

• [Journal Article] Possibility of the regression of atherosclerosis through the prevention of endothelial senescence by the regulation of nitric oxide and free radical scavengers (2010)
  • Author(s): Hayashi T, Iguchi A
  • Journal Title: Geriatr Gerontol Int. (印刷中)
  • Peer Reviewed
• [Journal Article] A hydroxymethylglutaryl coenzyme a reductase inhibitor improves endothelial function within 7 days in patients with chronic hemodialysis. (2010)
  • Author(s): Kishimoto N, Hayashi T, Sakuma I, Kano-Hayashi H, Tsunekawa T, Osawa M, Ina K, Iguchi A.
  • Journal Title: Int J Cardiol. (印刷中)
  • Peer Reviewed
• [Journal Article] Beneficial effect of the oligomerized polyphenol oligonol on high glucose-induced changes in eNOS phosphorylation and dephosphorylation in endothelial cells. (2010)
  • Author(s): Zhang XH, Yokoo H, Nishioka H, Fujii H, Matsuda N, Hayashi T, Hattori Y.
  • Journal Title: Br J Pharmacol (印刷中)
  • Peer Reviewed
• [Journal Article] Age-Associated Increase in Abdominal Obesity and Insulin Resistance, and Usefulness of AHA/NHLBI Definition of Metabolic Syndrome for Predicting Cardio-vascular Disease in Japanese Elderly with Type 2 Diabetes Mellitus (2010)
  • Author(s): Sakurai T, Iimuro S, Araki A, Umegaki H, Ohashi Y, Yokono K Ito H
  • Journal Title: Gerontology (印刷中)
  • Peer Reviewed
• [Journal Article] Pathophysiology of cognitive dysfunction in older people with type 2 diabetes : vascular changes or neurodegeneration? (2010)
  • Author(s): Umegaki H,
  • Journal Title: Age Ageing. 39 Pages: 8-10.
  • Peer Reviewed
• [Journal Article] Low HDL cholesterol is associated with the risk of stroke in elderly diabetic individuals : changes in the risk for atherosclerotic diseases at various ages. (2009)
  • Author(s): Hayashi T, Kawashima S, Itoh H, (他9名1番目), on behalf of Japan CDM group
  • Journal Title: Diabetes Care 32 Pages: 1221-1223
  • Peer Reviewed
• [Journal Article] Clinical factors such as B-type natriuretic peptide link to fact or VII, endothelial NO synthase and estrogen receptor alphapolymorphism in elderly women. (2009)
  • Author(s): Funami J, Hayashi T, Nomura H, Ding QF, Ishitsuka-Watanabe A, Matsui-Hirai H, Ina K, Zhang J, Yu ZY, Iguchi A.
  • Journal Title: Life Sciences 85 Pages: 316-321
  • Peer Reviewed
• [Journal Article] Acute metabolic responses to a high-carbohydrate meal in outpatients with type 2 diabetes treated with a low-carbohydrate diet : a crossover meal tolerance study. (2009)
  • Author(s): Haimoto H, Sasakabe T, Umegaki H, Wakai K
  • Journal Title: Nutr Metab(Lond). 6 Pages: 52
  • Peer Reviewed
• [Journal Article] Association of higher carbohydrate intake with depressive mood in elderly diabetic women. (2009)
  • Author(s): Umegaki H, Iimuro S, Araki A, Sakurai T, Iguchi A, (他3名1番目)
  • Journal Title: Nutr Neurosci. 12 Pages: 267-271
  • Peer Reviewed
• [Journal Article] (2009)
  • Author(s): Hayashi T, Iguchi A.
  • Journal Title: Free radicals as atherosclerotic risk-The relation of NO(Chapter 21)(Elsevier Co. Ltd.) Pages: 673-703(901)
• [Presentation] Interactions of glucose and insulin in regulation of replicative and stress-induced endothelial senescence-The relationship between telomere and nitric oxide- (2009)
  • Author(s): Hayashi T.Mastsui-Hirai H
  • Organizer: America's Gerontology Society 62nd Annual Scientific Meeting
  • Place of Presentation: Atlanta, USA
  • Year and Date: 2009-11-19
• [Presentation] Depression, Quality of Life and Living will of community-dwelling postmen opausal and elderly women in three asian countries, Japan, Korea and China. (2009)
  • Author(s): Ina K, Hayashi T
  • Organizer: 19^<th> IAGG World Congress of Gerontology and Geriatrics
  • Place of Presentation: Paris, France
  • Year and Date: 2009-07-06
• [Presentation] Low HDL-cholesterol is associated with the stroke risk in elderly diabetic individuals. (2009)
  • Author(s): Hayashi T, (他10名1番目)
  • Organizer: 19^<th> IAGG World Congress of Gerontology and Geriatrics
  • Place of Presentation: Paris, France
  • Year and Date: 2009-07-05
• [Presentation] Low HDL- cholesterol is associated with the risk of stroke in elderly diabetic individuals : Changes in the risk for atherosclerotic diseases at various ages. (2009)
  • Author(s): Hayashi T., (他10名1番目)
  • Organizer: American Diabetes Association's 69th Scientific Sessions
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2009-06-06
• [Presentation] A new view of atherosclerosis related pharmacogenetics based gene analysis in Japanese elderly women. (2009)
  • Author(s): K Ina, T.Hayashi
  • Organizer: The 10^<th> International Symposium on Mechanisms of Vasodiatation
  • Place of Presentation: Matsushima, Miyagi, JAPAN
  • Year and Date: 2009-06-02
• [Presentation] Biphsic effects of insulin on endothelial senescence. (2009)
  • Author(s): K Ina, T.Hayashi
  • Organizer: The 10^<th> International Symposium on Mechanisms of Vasodiatation
  • Place of Presentation: Matsushima, Miyagi, JAPAN
  • Year and Date: 2009-06-02
• [Presentation] 糖尿病罹患者における脳卒中リスクとしての脂質の影響-年齢による危険因子の変化- (2009)
  • Author(s): 伊奈孝一郎、林登志雄
  • Organizer: 第52回日本糖尿病学会学術集会優秀演題
  • Place of Presentation: 大阪
  • Year and Date: 2009-05-23
• [Presentation] 血管内皮細胞老化におけるグルコースとインシュリンの役割 (2009)
  • Author(s): 林登志雄, (他3名1番目)
  • Organizer: 第52回日本糖尿病学会学術集会優秀演題
  • Place of Presentation: 大阪
  • Year and Date: 2009-05-22
• [Presentation] 「シトルリン・疾患治療への応用と展望」シトルリン～NO産生と動脈硬化予防への展望 (2009)
  • Author(s): 林登志雄
  • Organizer: 第9回日本NO学術集会 セミナー
  • Place of Presentation: 静岡
  • Year and Date: 2009-05-09
• [Presentation] グルコースとインスリンの細胞老化ストレスを介する動脈硬化への作用 (2009)
  • Author(s): 林登志雄
  • Organizer: 第9回日本NO学術集会 シンポジウムNOとインスリン抵抗性-糖尿病・老化)
  • Place of Presentation: 静岡
  • Year and Date: 2009-05-08
• [Presentation] The role of glucose and insulin on endothelial senescence-The relation of diversity effect of insulin and telomerase- (2009)
  • Author(s): Hayashi T., (他3名1番目)
  • Organizer: Annual Scientific Meeting American Geriatrics Society
  • Place of Presentation: Chicago USA
  • Year and Date: 2009-05-03
• [Patent(Industrial Property Rights)] シトルリンとNO (2009)
  • Inventor(s): 林登志雄, (他2名1番目)
  • Industrial Property Rights Holder: 林登志雄, (他2名1番目), 名古屋大学
  • Industrial Property Number: 2007P00056
  • Acquisition Date: 2009-10-10