Regulation of mitochondrial ROS signaling in the cardiovascular stress response

2012 Fiscal Year Final Research Report

• Project Area: Signaling functions of reactive oxygen species
• Project/Area Number: 20117004
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Hokkaido University
• Principal Investigator: TSUTSUI Hiroyuki 北海道大学, 大学院・医学研究科, 教授 (70264017)
• Co-Investigator(Kenkyū-buntansha): MAKITA Naomasa 北海道大学, 大学院・医学研究科, 准教授 (00312356) ; KINUGAWA Shintaro 北海道大学, 大学院・医学研究科, 講師 (60399871) ; MATSUI Yutaka 北海道大学, 遺伝子病制御研究所, 特任准教授 (30431381) ; ISHIMORI Naoki 北海道大学, 大学院・医学研究科, 助教 (70399848) ; HATAKEYAMA Shigetsugu 北海道大学, 大学院・医学研究科, 教授 (70294973)
• Project Period (FY): 2008 – 2012
• Keywords: ミトコンドリア / 酸化ストレス / 活性酸素 / 心血管病 / ストレス応答

Research Abstract

The role of mitochondria in maintaining the biological function is dynamically regulated by mitochondrial DNA (mtDNA), a closed-circular double-stranded DNA molecule of～16.5 kb. MtDNA decline, mitochondrial defects, and mitochondrial oxidative stress are now well recognized in a variety of diseases such as neurodegenerative diseases, diabetes mellitus, cancer, and even aging. The present study clarified the crucial role of mitochondrial transcription factor A (TFAM) in cardiovascular stress response. With further knowledge on the mechanisms of TFAM for maintenance of mtDNA copy number and mitochondrial function, it may eventually be possible to develop novel strategies for the treatment ofcardiovascular diseases including heart failure.

Research Products

• [Journal Article] Type II NKT cells stimulate diet-induced obesity by mediating adipose tissue inflammation, steatohepatitis and insulin resistance (2012)
  • Author(s): Satoh M, Andoh Y, Clingan C S, Ogura H, Fujii S, Eshima K, Nakayama T, Taniguchi M,Hirata N, Ishimori N, Tsutsui H, Onoe K, Iwabuchi K
  • Journal Title: PLoS ONE Volume: 7(2) Pages: e30568
  • DOI: DOI:10.1371
  • Peer Reviewed
• [Journal Article] Angiotensin II-induced reduction in exercise capacity is associated with increased oxidative stress in skeletal muscle (2012)
  • Author(s): Inoue N,.Kinugawa S, Suga T, Yokota T, Hirabayashi K, Kuroda S, Okita K, Tsutsui H
  • Journal Title: Am J Physiol Heart Cire Physiol Volume: 302 Pages: Hl202-Hl210
  • DOI: DOI:10.1152
  • Peer Reviewed
• [Journal Article] Conduction and refractory disorders in the diabetic atrium (2012)
  • Author(s): Watanabe M, Y6ko shiki H, Mitsuyama H, Mizukami K, Ono T, Tsutsui H
  • Journal Title: Am J Physiol Heart Circ Physiol Volume: 303(1) Pages: H86-95
  • DOI: DOI:10.1152
  • Peer Reviewed
• [Journal Article] Activation ofnatural killer T cells ameliorates postinfarct cardiac remodeling and failure in mice (2012)
  • Author(s): Sobirin MA,.Kinugawa S, Takahashi M, Fukushima A, Homma T, Ono T, Hirabayashi K, Suga T, Azalia P, Takada S, Taniguchi M, Nakayama T, Ishimori N, Iwabuchi K, Tsutsui H
  • Journal Title: Circ Res Volume: 111(8) Pages: 1037-47
  • DOI: DOI:10.1161
  • Peer Reviewed
• [Journal Article] Interleukin-17A deficiency accelerates unstable atherosclerotic plaque fbrmation in apolipoprotein E-deficient mice (2012)
  • Author(s): Danzaki K, Matsui Y, Ikesue M, Ohta D, Ito K, Kanayama M, Kurotaki D, Morimoto J, Iwakura Y, Yagita H, Tsutsui H, Uede T
  • Journal Title: Arterioscler Thromb Vasc Biot Volume: 32(2) Pages: 273-80
  • DOI: DOI:10.1161
  • Peer Reviewed
• [Journal Article] Syndecan-4 prevents cardiac rupture and dysfunction after myo cardial infarction (2011)
  • Author(s): Matsui Y, Ikesue M, Danzaki K, Morimoto J, Sato M, Tanaka S, Koj ima T, Tsutsui H, Uede T
  • Journal Title: Circ Res Volume: 108(11) Pages: 1328-1339
  • DOI: DOI:10.1161
  • Peer Reviewed
• [Journal Article] Oxidative stress impairs insulin signal in skeletal muscle and causes insulin resistance in postinfarct heart failure (2011)
  • Author(s): Ohta Y, Kinugawa S,Matsushima S, Ono T, Sobirin MA, Inoue N, Yokota T, Hirabayashi K, Tsutsui H
  • Journal Title: Am J Physiot Heart Circ Physiol Volume: 300(5) Pages: Hl637-44
  • DOI: DOI:10.1152
  • Peer Reviewed
• [Journal Article] Syndecan-4 deficiency limits neointimal formation after vascular inj ury by regulating vascular smooth muscle cell proliferation and vascular progenitor cell mobilization (2011)
  • Author(s): Ikesue M, Matsui Y, Ohta D, Danzaki K, Ito K, Kanayama M, Kurotaki D, Morimoto J, Koj ima T, Tsutsui H, Uede T
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 31(5) Pages: 1066-1074
  • DOI: DOI:10.1161
  • Peer Reviewed
• [Journal Article] Nifedipine treatment reduces brain damage after transient focal ischemia, possibly through its antioxidative effects (2011)
  • Author(s): Yamato M, Shiba T, Ide T, Honda Y, Yamada K, Tsutsui H
  • Journal Title: Hypertens Res Volume: 34(7) Pages: 840-845
  • DOI: DOI:10.1038
  • Peer Reviewed
• [Journal Article] Lower aerobic capacity was associated with abnormal intramuscular energetics in patients with metabolic syndrome (2011)
  • Author(s): Yokota T, Kinugawa S, Okita K, Hirabayashi K, Suga T, Hattori M, Nakagawa Y, Oyama-Manabe N, Shirato Tsutsui H
  • Journal Title: Hypertens Res Volume: 34(9) Pages: 1029-34
  • DOI: DOI:10.1038
  • Peer Reviewed
• [Journal Article] High-fat diet-induced obesity and insulin resistance were meliorated via enhanced fecal bile acid excretion in tumor necrosis factor-alpha receptor knockout mice (2011)
  • Author(s): Yamato M, Shiba T, Ide T, Seri N, Kudo W, Ando M, Yamada K, Kinugawa S, Tsutsui H
  • Journal Title: Mol Cetl-Biochem Volume: 359(1-2) Pages: 161-7
  • DOI: DOI:10.1007
  • Peer Reviewed
• [Journal Article] Oxidative stress in cardiac and skeletal muscle dysfunction associated with diabetes mellitus (2011)
  • Author(s): Tsutsui H, Kinugawa S, Matsushima S, Yokota T
  • Journal Title: J Ctin Biochem Nutr Volume: 48(1) Pages: 68-71
  • DOI: DOI:10.3164
  • Peer Reviewed
• [Journal Article] Oxidative stress and heart failure (2011)
  • Author(s): Tsutsui H, Kinugawa S, Matsushima S
  • Journal Title: Am J Physiol Heart Cire Physiot Volume: 301(6) Pages: H2181-90
  • DOI: DOI:10.1152
  • Peer Reviewed
• [Journal Article] Natural killer T Cells are involved in adipose tissues inflammation and glucose intolerance in diet-lnduced obese mice (2010)
  • Author(s): Ohmura K, Ishimori N, Ohmura Y, Tokuhara S, Nozawa A, Horii S, Andoh Y, Fujii S, Iwabuchi K, Onoe K, Tsutsui H
  • Journal Title: Arterioscler Thromb Vasc Biot Volume: 30(2) Pages: 193-199
  • DOI: DOI:10.1161
  • Peer Reviewed
• [Journal Article] Overexpression of mitochondrial transcription factor A (TFAM)ameliorates delayed neuronal death due to transient orebrain ischemia in mice (2010)
  • Author(s): Hokari M, Kuroda S, Kinugawa S, Ide T, Tsutsui H, Iwasaki Y
  • Journal Title: Neuropathotogy Volume: 30(4) Pages: 401-407
  • DOI: DOI:10.1111
  • Peer Reviewed
• [Journal Article] High mitochondrial DNA copy number has detrimental effects in mice (2010)
  • Author(s): Ylikallio E, Tyynismaa H, Tsutsui H, Ide T, Suomalainen A
  • Journal Title: Hum Mol Genet Volume: 19(13) Pages: 2695-2705
  • DOI: DOI:10.1093
  • Peer Reviewed
• [Journal Article] Time-dependent changes of myocardial and systemic oxidative stress are dissociated after myocardial infarction (2009)
  • Author(s): Inoue T, Ide T, Yamato M, Yoshida M, Tsutsumi T, Andou M, Utsumi H, Tsutsui H, Sunagawa K
  • Journal Title: Free-Radic Res Volume: 43(1) Pages: 37-46
  • DOI: DOI:10.1080
  • Peer Reviewed
• [Journal Article] Increased myocardial NAD(P)H oxidase-derived superoxide causes the exacerbation ofpost-infarct heart failure in type 2 diabetes (2009)
  • Author(s): Matsushima S,.Kinugawa S, Y6kota T, Inoue N, Ohta Y, Hamaguchi S, Tsutsui H
  • Journal Title: Am J Physiol Heart Circ Physiol Volume: 297(1) Pages: 409-416
  • DOI: DOI:10.1152
  • Peer Reviewed
• [Journal Article] Oxidative stress in skeletal muscle impairs mitochondrial respiration and limits exercise capacity in type 2 diabetic mice (2009)
  • Author(s): Yokota T, Kinugawa S, Hirabayashi K, Matsushima S, Inoue N, Ohta Y, Hamaguchi S, Sobirin A, Ono T, Suga T, Kuroda S, Tanaka S, Terasaki F, Okita K, Tsutsui H
  • Journal Title: Am J Physiol Heart Circ Physiol Volume: 297(3) Pages: 1069-1077
  • DOI: DOI:10.1152
  • Peer Reviewed
• [Journal Article] Mitochondrial oxidative stress and dysfunction in myocardial remodelling (2009)
  • Author(s): Tsutsui H, Kinugawa S, Matsushima S
  • Journal Title: Cardiovasc Res Volume: 81(3) Pages: 449-456
  • DOI: DOI:10.1093
  • Peer Reviewed
• [Journal Article] The E1784K mutation in SCN5Ais associated with mixed clinical phenotype oftype 3 long QT syndrome (2008)
  • Author(s): Makita N, Behr E, Shimizu W, Horie M, Sunami A, Crotti L, Schulze-Bahr E, Fukuhara, S, Mochizuki N, akiyama T, Itoh H, Christiansen M, McKeown P, Miyamoto K, Kamakura S, Tsutsui H, Schwartz PJ, George AL Jr, Roden DM
  • Journal Title: J Ctin Invest Volume: 118(6) Pages: 2219-2229
  • DOI: DOI:10.1172
  • Peer Reviewed
• [Journal Article] Modulation ofthe myocardial redox state by vagal nerve stimulation after experimental myocardial infarction (2008)
  • Author(s): Tsutsumi T, Ide T, Yamato M, Kudou W, Andou M, Hirooka Y, Utsumi H, Tsutsui H, Sunagawa K
  • Journal Title: Cardiovasc Res Volume: 77(4) Pages: 713-721
  • DOI: DOI:10.1093
  • Peer Reviewed
• [Journal Article] Reverse ofage-dependent memory impairment and mitochondrial DNA damage in microglia by an overexpression ofhuman itochondrial transcription factor ain mice (2008)
  • Author(s): Hayashi Y, Yoshida M, Yamato M, Ide T, Wu Z, Ochi-Shindou M, Kanki T, Kang D, Sunagawa K, Tsutsui H, Nakanishi H
  • Journal Title: J Neurosci Volume: 28(34) Pages: 8624-8634
  • DOI: DOI:10.1523
  • Peer Reviewed
• [Journal Article] Oxidative stress and mitochondrial DNA damage in heart failure (2008)
  • Author(s): Tsutsui H, Kinugawa S, Matsushima S
  • Journal Title: Circ J Suppl Volume: A Pages: A-31-A-37
  • DOI: DOI:10.1152
  • Peer Reviewed
• [Presentation] 心血管病におけるミトコンドリア酸化ストレスの役割 (2009)
  • Author(s): 筒井裕之
  • Organizer: 第82回日本薬理学会年会
  • Place of Presentation: パシフイコ横浜,横浜
  • Year and Date: 2009-03-16
• [Presentation] メタボリックシンドローム・心血管病と骨格筋機能不全 (2008)
  • Author(s): 筒井裕之
  • Organizer: 第19回日本臨床スポーツ医学会学術集会
  • Place of Presentation: 幕張メッセ,千葉
  • Year and Date: 2008-11-02
• [Presentation] 心不全の病態をふまえた治療戦略～理想的な周術期管理の実践のために～ (2008)
  • Author(s): 筒井裕之
  • Organizer: 日本心臓血管麻酔学会第13回学術大会
  • Place of Presentation: 沖縄コンベンションセンター,沖縄
  • Year and Date: 2008-11-01
• [Presentation] 心保護を目指した高血圧の治療戦略 (2008)
  • Author(s): 筒井裕之
  • Organizer: 第31回日本高血圧学会総会
  • Place of Presentation: ロイトン札幌,札幌
  • Year and Date: 2008-10-10
• [Presentation] 北大が目指す循環器内科の将来展望 (2008)
  • Author(s): 筒井裕之
  • Organizer: 第100回日本循環器学会北海道地方会
  • Place of Presentation: 北翔大学,札幌
  • Year and Date: 2008-09-20
• [Presentation] 心腎連関をふまえた心血管病の治療戦略 (2008)
  • Author(s): 筒井裕之
  • Organizer: 第56回日本心臓病学会学術集会
  • Place of Presentation: 東京国際フォーラム,東京
  • Year and Date: 2008-09-09
• [Presentation] 心血管病におけるミトコンドリア酸化ストレスの役割 (2008)
  • Author(s): 筒井裕之
  • Organizer: 第61回日本酸化ストレス学会学術集会
  • Place of Presentation: 国立京都国際会館,京都
  • Year and Date: 2008-06-19
• [Presentation] 心血管リモデリング制御と高血圧・心不全治療 (2008)
  • Author(s): 筒井裕之
  • Organizer: 第19回日本心エコー図学会学術集会
  • Place of Presentation: 神戸ポートピアホテル,神戸
  • Year and Date: 2008-04-12
• [Book] 知のフロンティア 北海道大学の研究者は、いま 第2号 (2012)
  • Author(s): 筒井裕之
  • Total Pages: 68-69
  • Publisher: 北海道大学アドミッションセンター
• [Book] 高血圧ナビゲーター (2011)
  • Author(s): 絹川真太郎,筒井裕之
  • Total Pages: 138-139
  • Publisher: メディカルレビュー社
• [Book] Cardio Diabetic Frontier～心血管病と糖尿病を統一的に理解する新たな視点を求めて～ (2010)
  • Author(s): 絹川真太郎,筒井裕之
  • Total Pages: 62-68
  • Publisher: メディカルレビュー社
• [Book] 循環器ストレス学 (2010)
  • Author(s): 絹川真太郎,筒井裕之
  • Total Pages: 265-272
  • Publisher: 南山堂
• [Book] 診療に活かす心機能評価 (2010)
  • Author(s): 横田卓,筒井裕之
  • Total Pages: 26-29
  • Publisher: 羊士社
• [Book] 活性酸素シグナルと酸化ストレス (2009)
  • Author(s): 井手友美,筒井裕之
  • Total Pages: 38-42
  • Publisher: 羊土社
• [Book] 高血圧ナビゲーター(第2版) (2008)
  • Author(s): 絹川真太郎、筒井裕之
  • Total Pages: 146-147
  • Publisher: メディカルレビュー社
• [Book] 酸化ストレスの医学 (2008)
  • Author(s): 絹川真太郎,筒井裕之
  • Total Pages: 230-239
  • Publisher: 診断と治療社