心筋細胞保護シグナルにおけるコネキシン43の役割

2010 年度 研究成果報告書

• 研究課題/領域番号: 20590870
• 研究種目: 基盤研究(C)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 循環器内科学
• 研究機関: 札幌医科大学
• 研究代表者: 三浦 哲嗣 札幌医科大学, 医学部, 教授 (90199951)
• 研究分担者: 三木 隆幸 札幌医科大学, 医学部, 講師 (00336405) ; 丹野 雅也 札幌医科大学, 医学部, 講師 (00398322)
• 研究期間 (年度): 2008 – 2010
• キーワード: コネキシン / 細胞シグナル / 心筋細胞 / 細胞死

研究概要

心筋細胞において細胞膜上のコネキシン43(Cx43)はG蛋白連関受容体のβサブユニットと相互作用することによってクラスIB PI3キナーゼ(PI3K)の活性化に寄与しており、PI3K-Akt-グリコーゲン合成酵素キナーゼ-3β経路の活性化、その結果としての細胞死抑制に必須な役割を果たしていることが明らかとなった。一方、ミトコンドリアATP感受性K^+チャネルの制御に寄与しているミトコンドリアCx43はG蛋白連関受容体によるPI3K-Akt活性化には関与していないことが示された。

研究成果

• [雑誌論文] Hypertensive hypertrophied myocardium is vulnerable to infarction and refractory to erythropoietin-induced protection. (2011)
  • 著者名/発表者名: Yano T, Miki T, Tanno M, Kuno A, Itoh T, Takada A, Sato T, Kouzu H, Shimamoto K, Miura T.
  • 雑誌名: Hypertension 57 ページ: 110-115
  • 査読あり
• [雑誌論文] Cytoskeletal proteins : hidden targets of cytoprotective signaling? (2010)
  • 著者名/発表者名: Miura T.
  • 雑誌名: Circ J 74 ページ: 2295-2296
  • 査読あり
• [雑誌論文] Erythropoietin (EPO) affords more potent cardioprotection by activation of distinct signaling to mitochondrial kinases compared with carbamylated EPO. (2010)
  • 著者名/発表者名: Sato T, Tanno M. Miki T, Yano T, Sato T, Shimamoto K, Miura T.
  • 雑誌名: Cardiovasc Drugs Ther 24 ページ: 401-408
  • 査読あり
• [雑誌論文] Roles of phospho-GSK-3β in myocardial protection afforded by activation of the mitochondrial K ATP channel. (2010)
  • 著者名/発表者名: Terashima Y, Sato T, Yano T, Maas O, Itoh T, Miki T, Tanno M, Kuno A, Shimamoto K, Miura T.
  • 雑誌名: J Mol Cell Cardiol 49 ページ: 762-770
  • 査読あり
• [雑誌論文] Mitochondria and GSK-3beta in cardioprotection against ischemia/reperfusion injury. (2010)
  • 著者名/発表者名: Miura T, Tanno M.
  • 雑誌名: Cardiovasc Drugs Ther 24 ページ: 255-263
  • 査読あり
• [雑誌論文] Role of the gap junction in ischemic preconditioning in the heart. (2010)
  • 著者名/発表者名: Miura T. Miki T. Yano T.
  • 雑誌名: Am J Physiol Heart Circ Physiol 298 ページ: H1115-H1125
  • 査読あり
• [雑誌論文] Epicardium and pericardium : a joint force for infarct repair? (2010)
  • 著者名/発表者名: Miura T.
  • 雑誌名: J Mot Cell Cardiol 48 ページ: 579-581
  • 査読あり
• [雑誌論文] Angiotensin II type 1 receptor-mediated upregulation of calcineurin activity underlies impairment of cardioprotective signaling in diabetic hearts. (2010)
  • 著者名/発表者名: Hotta H, Miura T. Miki T, Togashi N, Maeda T. Kim SJ, Tanno M Yano T, Kuno A, Itoh T, Satoh T, Terashima Y, Ishikawa S, Shimamoto K.
  • 雑誌名: Circ Res 106 ページ: 129-132
  • 査読あり
• [雑誌論文] Endoplasmic reticulum stress in diabetic hearts abolishes erythropoietin-induced myocardial protection by impairment of phospho-glycogen synthase kinase-3β-mediated suppression of mitochondrial permeability transition. (2009)
  • 著者名/発表者名: Miki T Miura T, Hotta H, Tanno M, Yano T, Sato T, Terashima Y, Takada A, Ishikawa S, Shimamoto K.
  • 雑誌名: Diabetes 58 ページ: 2863-2872
  • 査読あり
• [雑誌論文] GSK-3β, a therapeutic target for cardiornyocyte protection. (2009)
  • 著者名/発表者名: Miura T Miki T.
  • 雑誌名: Circ J 73 ページ: 1184-1192
  • 査読あり
• [雑誌論文] Drug development targeting the glycogen synthase kinase-3β (GSK-3β)-mediated signal transduction pathway : role of GSK-3β in myocardial protection against ischemia/reperfusion injury. (2009)
  • 著者名/発表者名: Miura T, Nishihara M, Miki T.
  • 雑誌名: J Pharmacol Sci 109 ページ: 162-167
  • 査読あり
• [雑誌論文] Roles of Cx43-associated protein kinases in suppression of gap junction-mediated chemical coupling by ischemic preconditioning. (2009)
  • 著者名/発表者名: Naitoh K, Yano T, Miura T, Itoh T, Miki T Tanno M Sato T, Hotta H, Terashima Y, Shimamoto K.
  • 雑誌名: Am J Physiol Heart Circ Physiol 296 ページ: H396-H403
  • 査読あり
• [雑誌論文] Ser9 phosphorylation of mitochondrial GSK-3β is a primary mechanism of cardiomyocyte protection by erythropoietin against oxidant-induced apoptosis. (2008)
  • 著者名/発表者名: Ohori K, Miura T, Tanno M, Miki T, Sato T, Ishikawa S, Horio Y, Shimamoto K.
  • 雑誌名: Am J Physiol Heart Circ Physiol 295 ページ: H2079-H2086
  • 査読あり
• [雑誌論文] Limitation of myocardial infarct size in the clinical setting : current status and challenges in translating animal experiments into clinical therapy. (2008)
  • 著者名/発表者名: Miura T, Miki T.
  • 雑誌名: Basic Res Cardiol 103 ページ: 501-513
  • 査読あり
• [雑誌論文] Adenine nucleotide translocator, a mitochondrial carrier protein, and fate of cardiomyocytes after ischaemia/reperfusion. (2008)
  • 著者名/発表者名: Tanno M, Miura T.
  • 雑誌名: Cardiovasc Res 80 ページ: 1-2
  • 査読あり
• [雑誌論文] Glycogen synthase kinase-3 inactivation is not required for ischemic preconditioning or postconditioning in the mouse. (2008)
  • 著者名/発表者名: Nishino Y, Webb IG, Davidson SM, Ahmed AI, Clark JE, Jacquet S, Shah AM, Miura T, Yellon DM, Avkiran M, Marber MS.
  • 雑誌名: Circ Res 103 ページ: 307-314
  • 査読あり
• [雑誌論文] Limitation of infarct size by erythropoietin is associated with translocation of Akt to the mitochondria after reperfusion. (2008)
  • 著者名/発表者名: Kobayashi H, Miura T. Ishida H, Miki T. Tanno M Yano T, Sato T, Hotta H, Shimamoto K.
  • 雑誌名: Clin Exp Pharmacol Physiol 35 ページ: 812-819
  • 査読あり
• [学会発表] Activation of Sirtl suppresses hypertrophic response of cardiomyocytes by inhibition of H3K9 acetylation via proteasome-mediated p300 degradation. (2010)
  • 著者名/発表者名: Kuno A, Tanno M, Ishikawa S, Horio Y, Miura T.
  • 学会等名: 83^<rd> Scientific Sessions of American Heart Association.
  • 発表場所: Chicago, USA.
  • 年月日: 20101113-20101117
• [学会発表] Connexin-43 contributes to transmission of MitoK_ATP channel-derived redox signal to Akt-GSK-3β pathway in cardiomyocyte protection afforded by G protein-coupled receptors. (2010)
  • 著者名/発表者名: Ishikawa S, Kuno A, Miki T, Tanno T. Yano T, Kouzu H, Sato T, Sunaga D, Miura T.
  • 学会等名: 83rd Scientific Sessions of American Heart Association.
  • 発表場所: Chicago, USA
  • 年月日: 20101113-20101117
• [学会発表] Ventricular dysfunction and blunted response to adrenergic stimulation in obese type 2 diabetes predispose to fatal heart failure after infarction : Possible involvement of microRNA-1 down-regulation. (2010)
  • 著者名/発表者名: Takada A, Miki T Tanno M, Suzuki H, Yano T, Kuno A, Itoh T, Sato T, Miura T.
  • 学会等名: 83rd Scientific Sessions of American Heart Association.
  • 発表場所: Chicago, USA
  • 年月日: 20101113-20101117
• [学会発表] Increased ER stress is a fundamental mechanism for impairment of cardioprotective signaling in type 2 diabetes. (2010)
  • 著者名/発表者名: Kouzu H, Itoh T, Miki T. Tanno M, Yano Y, Sato T, Takada A, Sunaga D, Miura T.
  • 学会等名: 83rd Scientific Sessions of American Heart Association.
  • 発表場所: Chicago, USA
  • 年月日: 20101113-20101117
• [学会発表] Connexin43-dependent mitochondrial GSK-3β phosphorylation in protection of cardiomyocyte against necrosis. (2010)
  • 著者名/発表者名: Ishikawa S, Miki T, Tanno M, Miura T.
  • 学会等名: 20th World Congress of the International Society for Heart Research.
  • 発表場所: Kyoto, Japan
  • 年月日: 20100513-20100516
• [学会発表] Enhancement of cyclophilin-D-ANT interaction upon reperfusion in hypertensive hypertrophied hearts : a target of cardioprotection against ischemia/reperfusion injury. (2010)
  • 著者名/発表者名: Yano T, Tanno M Itoh T, Miura T.
  • 学会等名: 20th World Congress of the International Society for Heart Research.
  • 発表場所: Kyoto, Japan
  • 年月日: 20100513-20100516
• [学会発表] Role of GSK-3β in negative regulation of the mPTPs by the mitochondrial K_ATP channel. (2010)
  • 著者名/発表者名: Itch T, Terashima Y, Miki T, Miura T, Shimamoto K.
  • 学会等名: 20th World Congress of the International Society for Heart Research.
  • 発表場所: Kyoto, Japan
  • 年月日: 20100513-20100516
• [学会発表] Mitochondria is a critical compartment for phospho-GSK-3β to afford cytoprotection against ischemia/reperfusion injury. (2010)
  • 著者名/発表者名: Sato T, Miura T, Tanno M, Miki T, Takada A, Itch T, Shimamoto K.
  • 学会等名: 20th World Congress of the International Society for Heart Research.
  • 発表場所: Kyoto, Japan
  • 年月日: 20100513-20100516
• [学会発表] Glycogen synthase kinase-3β as a therapeutic target for cardiomyocyte protection. (2010)
  • 著者名/発表者名: Miura T. Miki T, Shimamoto K.
  • 学会等名: 20th World Congress of the International Society for Heart Research.
  • 発表場所: Kyoto, Japan
  • 年月日: 20100513-20100516
• [学会発表] Role of GSK-3β in negative regulation of mitochondrial permeability transition pore by the mitochondrial K_ATP channel. (2009)
  • 著者名/発表者名: Miura T, Terashima Y, Maas O, Miki T, Tanno M, Ishikawa S, Shimamoto K.
  • 学会等名: 31st Congress of the European Society of Cardiology.
  • 発表場所: Barcelona, Spain
  • 年月日: 20090829-20090902
• [学会発表] Enhanced ANT-cyclophilin-D interaction underlies reduced anti-infarct tolerance and loss of protective response to erythropoietin in hypertensive hypertrophied hearts. (2009)
  • 著者名/発表者名: Miki T. Yano T, Miura T, Tanno M. Shimamoto K.
  • 学会等名: 31st Congress of the European Society of Cardiology.
  • 発表場所: Barcelona, Spain
  • 年月日: 20090829-20090902
• [学会発表] Jak2-mediated cardioprotective signaling is impaired in diabetic hearts by AT_1 receptormediated up-regulation of calcineurin. (2009)
  • 著者名/発表者名: Miura T, Hotta H, Miki T, Yano T, Ishikawa S, Shimamoto K.
  • 学会等名: 31st Congress of the European Society of Cardiology.
  • 発表場所: Barcelona, Spain
  • 年月日: 20090829-20090902
• [学会発表] Activation of histone/protein deacetylase SIRTI by resveratrol induces MnSOD upregulation via FOXO3a and improves survival of heart failure animals. (2009)
  • 著者名/発表者名: Kuno A, Tanno M. Miura T, Horio Y, Shimamoto K.
  • 学会等名: 31st Congress of the European Society of Cardiology.
  • 発表場所: Barcelona, Spain
  • 年月日: 20090829-20090902
• [学会発表] ER stress contributes to dysregulation of GSK-3β-mediated suppression of mitochondrial permeability transition in diabetic hearts. (2008)
  • 著者名/発表者名: Miki T, Tanno M, Kuno A, Yano T, Sato T, Hotta H, Ichikawa S, Miura T.
  • 学会等名: 81st Scientific Sessions of American Heart Association.
  • 発表場所: New Orleans, USA.
  • 年月日: 20081108-20081112
• [学会発表] Connexin43-dependent and-independent mechanisms of mitochondrial GSK-3β phosphorylation in protection of cardiomyocyte against necrosis. (2008)
  • 著者名/発表者名: Ishikawa S, Miura T, Tanno M, Kuno A, Sato T, Hotta H, Terashima Y, Miki T.
  • 学会等名: 81st Scientific Sessions of American Heart Association.
  • 発表場所: New Orleans, USA.
  • 年月日: 20081108-20081112
• [学会発表] Activation of a protein deacetylase, SIRTI, by Resveratol suppresses progression of heart failure and improves survival by up-regulation of Mn-SOD. (2008)
  • 著者名/発表者名: Tanno M Kuno A, Miki T. Miura T. Horio Y, Shimamoto K.
  • 学会等名: 81st Scientific Sessions of American Heart Association.
  • 発表場所: New Orleans, USA.
  • 年月日: 20081108-20081112
• [学会発表] Resveratrol, an activator of protein deacetylase SIRT1, suppresses oxidative stress-induced cell death by upregulating MnSOD expression through transactivation of Foxo3a. (2008)
  • 著者名/発表者名: Kuno A, Tanno M Miura T, Horio Y, Shimamoto K.
  • 学会等名: 81st Scientific Sessions of American Heart Association.
  • 発表場所: New Orleans, USA.
  • 年月日: 20081108-20081112
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