2000 Fiscal Year Annual Research Report

心臓血管系におけるチャネル病の発症と成因に関する調査・研究

Research Project

Project/Area Number	12897010
Research Institution	Tokyo Medical and Dental University
Principal Investigator	平岡昌和東京医科歯科大学, 難治疾患研究所, 教授 (80014281)
Co-Investigator(Kenkyū-buntansha)	大津欣也大阪大学, 大学院・医学研究科, 助手 (20294051) 木村彰方東京医科歯科大学, 難治疾患研究所, 教授 (60161551) 堀江稔京都大学, 大学院・医学研究科, 講師 (90183938) 児玉逸雄名古屋大学, 環境医学研究所, 教授 (30124720) 岡田泰伸岡崎国立共同研究機構, 生理学研究所, 教授 (10025661)
Keywords	QT延長症候群 / チャネル遺伝子 / 特発性心室細動 / Ca感受性 / Ca遊離チャネル / Gap junction / 電気的リモデリング / 分化誘導
Research Abstract	遺伝性QT延長症候群のチャネル遺伝子変異による機能障害の程度と抑制機序の違い、臨床像の差異を明らかにした(平岡、堀江)。特発性心室細動のBrugada症候群の全国調査を行い、類似の症例が約1000例近いこと、Brugada症候群を含む特発性心室細動に認められたNaチャネル遺伝子変異の機能低下を見出した(平岡、蒔田)。Brugada症候群に特異的な心電図右胸部誘導でのST上昇の機序を検討、一過性外向き電流の増大、Na電流・Ca電流の減少の関与を明らかにした(清水)。心筋特異的に発現するミオシン軽鎖リン酸化酵素サブユニットが心筋収縮のCa感受性を亢進させ、これを高発現するトランスジェニックマウスの一部に心肥大、徐脈と突然死を認め、Ca感受性亢進が心肥大・不整脈発生の原因となりうることを明らかにした(木村)。遺伝性高血圧疾患・Liddle症候群につき、上皮型Naチャネル(ENaC)の遺伝子変異を解析して、.サブユニットや.サブユニット遺伝子に変異を認めた(佐々木)。心筋小胞体Ca遊離チャネルやその結合蛋白質の心筋特異的遺伝子改変マウスを作成、機能を解析した(大津)。パーキンソン病様症状を示すwvマウスの原因遺伝子であるG蛋白質制御型(K_G)チャネル分子Kir3.2はG蛋白質非感受性であるが、PDZ蛋白質共存下で感受性を示し、その相互作用はチャネルの活性を制御することが推測された(稲野辺)。容積調節能(RVD)に関与する容積調節性Clチャネルの活性異常が虚血性心筋細胞死やアポトーシス発生に関与する知見を見いだした(岡田)。発作性心房細動の電気的リモデリングは2相性Kv1.5チャネル発現変化を示し、早期相のKv1.5チャネル発現はCAMKIIおよびp38MAPK燐酸化を介したCREB燐酸化、後期相はFos/Jun蛋白生成によるAP-1による転写促進に関連した(山下)。ヒト心房筋細胞の再分極相に働く一過性K電流(Ito)、ultra rapid型K電流(IKur)に対し、新規抗不整脈薬・NIP-141はIKurにはIC50値が5μMとIto(17μM)より低濃度で抑制した(萩原)。右室肥大(RVH)・左室肥大(LVH)ラットを用い圧負荷心肥大に伴う心室筋gap junctionの発現・分布の変化(リモデリング)を検討、Connexin43(Cx43)は1)細胞長軸端の介在板部分に限局せず細胞全体に広く分布する、2)介在板中央部分の小型gap junctionが減少する、3)伝導の異方性が減弱した(児玉)。骨髄間葉系幹細胞由来の心筋芽細胞(CMG細胞)を分化誘導し、分化誘導の時期により活動電位波形やチャネル発現が変化した(小川)。

Research Products
(49 results)

All Other

All Publications (49 results)

[Publications] Terai T: "Effects of external acidosis on HERG current expressed in Xenopusoocytes."J Mol Cell Cardiol. 32. 11-21 (2000)
[Publications] Nakajima T: "Characterization of S818L mutation in HERG C-terminus in LQT2. Modification on activation-deactivation gating properties."FEBS Leter. 481. 197-203 (2000)
[Publications] Moncada GA: "Effects of acidosis and NO on nicorandil-activated K_<ATP> channels in guinea-pig ventricular myocytes."Br J Pharmacol.. 131. 1097-1104 (2000)
[Publications] Akai J: "A novel SCN5A mutation associated with idiopathic ventricular fibrillation without typical ECG findings of Brugada syndrome."FEBS Letter. 479. 29-34 (2000)
[Publications] Hiraoka M: "Functional abnormalities of HERG channel mutations in LQT2."Jpn J Electrocardiol.. 20(Suppl3). 129-125 (2000)
[Publications] Makita N: "Cardiac Na^+ channel dysfunction in the Brugada syndrome is aggravated by β1 Subunit"Circulation. 101. 54-60 (2000)
[Publications] Wang DW: "Enhanced sodium channel intermediate inactivation in Brugada syndrome"Circulation Research. 87. E37-E43 (2000)
[Publications] Shimizu W: "Body surface distribution and response to drugs of ST segment elevation in the Brugada syndrome : Clinical implication of 87-leads body surface potential mapping and its application to 12-leads electrocardiograms."J Cardiovasc Electrophysiol. 11. 396-404 (2000)
[Publications] Yoshida H: "Characterization of a novel missense mutation in the pore region of HERG in a long QT syndrome."J Cardiovas Electrophysiol. 10. 1262-1270 (1999)
[Publications] Obayashi K: "On the mechanism of genistein-induced activation of protein kinase A-dependent Cl^- conductance in cardiac myocytes."Pflugers Archiv. 438. 269-277 (1999)
[Publications] Xie LH: "Phospholipase C-linked receptors regulate the ATP-sensitive potassium channel via depletion of phosphatidylinositol-4,5-biphosphate."Proc Natl Acad Sci USA. 96. 15292-15297 (1999)
[Publications] Horie M: "Blockade of cardiac ATP-sensitive K^+ channels by cibenzoline targets its pore-forming subunit."J Cardiovasc Pharmacol. 35. 434-422 (2000)
[Publications] Kono Y: "The properties of Kir6.1-6.2 tandem channel co-expressed with SUR2A."Pflugers Archiv Eur J Physiol. 440. 692-698 (2000)
[Publications] Haruna T: "Alteration of membrane lipid environment by 1-palmitoylcarnitine modulates K_<ATP> channels in guinea pig ventricular myocytes."Pflugers Archiv Eur J Physiol. 441. 200-207 (2000)
[Publications] Kubota T: "Hypokalemia-induced long QT syndrome with an underlying novel missense mutation in S4-S5 linker of KCNQ1."J Cardiovasc Electrophysiol. 11. 1048-54 (2000)
[Publications] Akao M: "Angiotensin II type 1 receptor blockade abolishes specific KATP channe gene exression in rats with myocardial infarction."J Mol Cell Cardiol. 32. 2239-2247 (2000)
[Publications] Yoshida H: "Bradycardia-induced long QT syndrome caused by a de novo missense mutation in the S2-S3 inner loop of HERG."Am J Human Genetics. 98. 348-352 (2001)
[Publications] Arimura T: "Characterization of human nebulette gene : A polymorphism in an actin-binding motif is associated with non-familial idiopathic dilated cardiomyopathy."Hum Genet. 107. 440-451 (2000)
[Publications] Lee WH: "Different expressivity of a ventricular essential light chain gene Ala57Gly mutation in familial hypertrophic cardiomyopathy."Am Heart J. (in press). (2001)
[Publications] Arimura T: "Identification, characterization and functional analysis of heart-specific myosin light chain phosphatase small subunit."J Biol Chem. (in press). (2001)
[Publications] Kimura A: "Molecular etiology of idiopathic cardiomyopathy in the Oriental populations."J Cardiol. (in press). (2001)
[Publications] Yamashita Y: "Two sporadic cases of Liddle syndrome caused by de novo ENaC mutations."Am J Kid Diseas. (2001)
[Publications] Date M: "Analysis on the -sarcoglycan Gene in Japanese Patients with Hypertrophic Cardiomyopathy."Am J Cardiol. 85. 1315-1318 (2000)
[Publications] Yamashita N: "The Involvement of Cytokines in the Mechanism of the Whole-body Hyperthermia-induced Cardioprotection"Circulation. 102. (2000)
[Publications] Hoshida S: "Cholesterol feeding exacerbates myocardial injury in Zucker diabetic fatty rats"Am J Physiol. 278. H256-H262 (2000)
[Publications] Sakata Y: "Calcineurin Inhibitor Attenuates Left Ventricular Hypertrophy, Leading to Prevention of Heart Failure in Hypertensive Rats."Circulation. 102. 2269-2275 (2000)
[Publications] Yamashita N: "The involvement of cytokines in the second window of ischemic preconditioning."Br J Pharmacol. (in press). (2001)
[Publications] Matsuoka,T: "C-Terminal tails of sulfonylurea receptors control ADP-induced activation and diazoxide modulation of ATP-sensitive K^+ channels."Circ.Res.. 87. 873-880 (2000)
[Publications] Fujita,S: "A regulator of G protein signalling (RGS) protein confers agonist-dependent relaxation gating to a G protein-gated K^+ channel."J Physiol. 526. 341-347 (2000)
[Publications] Tanemoto,M: "In vivo formation of a proton-sensitive K^+ channel by heteromeric subunit assembly of Kir5.1 with Kir4.1."J Physiol. 525. 587-592 (2000)
[Publications] Hibino,H: "Anchoring proteins confer G protein sensitivity to an inward-rectifier K^+ channel through the GK domain."EMBO J. 19. 78-83 (2000)
[Publications] Hazama A: "Swelling-activated, cystic fibrosis transmembrane conductance regulator-augmented ATP release and Cl^- conductances in C127 cells."J.Physiol.( London ). 523. 1-11 (2000)
[Publications] Morishima S: "Volume expansion sensitivity of swelling-activated Cl^- channel in human epithelial cells."Jpn J Physiol. 50. 277-280 (2000)
[Publications] Maeno E: "Normotonic cell shrinkage due to disordered volume regulation is an early prerequisite to apoptosis."Proc Natl Acad Sci USA. 97. 9487-9492 (2000)
[Publications] Shimizu S: "Ca^<2+>-sensing receptor-mediated regulation of volume-sensitive Cl^- channels in human epithelial cells."J.Physiol.(London). 528. 457-472 (2000)
[Publications] Yamashita T: "Short-term effects of rapid pacing on the mRNA levels of voltage-dependent K+ channels in the rat atrium : electrical remodeling in paroxysmal atrial tachycardia."Circulation. 101. 2007-2014 (2000)
[Publications] Kajimoto K: "Efficacy of continuous intravenous drip infusion of disopyramide in hypertrophic obstructive cardiomyopathy during cardiogenic shock."J Cardiol. 35. 197-203 (2000)
[Publications] Uzzaman M: "Remodeling of gap junctional coupling in hypertrophied right ventricles of rats with monocrotaline-induced pulmonay hypertension."Circ Res. 86. 871-878 (2000)
[Publications] Kodama I: "Gap junction remodeling in hypertrophied cardiac muscle."Jpn J Electrocardiology. 20(S3). 93-98 (2000)
[Publications] Emdad L: "Gap junction remodeling in hypertrophied left ventricles of aortic-banded rats : prevention by angiotensin II type 1 receptor blockade."J Mol Cell Cardiol. 33. 219-231 (2001)
[Publications] Kato T: "Calmodulin kinase-II, -IV and calcineurin are involved in leukemia inhibitory factor-induced cardiac hypertrophy in rats."Circ Res. 87. 937-945 (2000)
[Publications] Kodama H: "Significance of Raf-1/MEK/ERK cascade compared with JAK/STAT and PI3-K Pathway in gp130-mediated Cardiac Hypertrophy."Am J Physiol. 279. H1635-H1644 (2000)
[Publications] Fukuda K: "Cardiomyocyte Cell Line To Overcome Fibrotic Myocardium."Microcirculation annual. 16. 17-18 (2000)
[Publications] Sano M: "IL-6 Family of cytokines mediate angiotensin II-induced cardiac hypertrophy in rodent cardiomyocytes."J Biol Chem. 275. 29717-29723 (2000)
[Publications] Sano M: "Autocrine/Paracrine Secretion of IL-6 Family Cytokines Causes Angiotensin II-Induced Delayed STAT3 Activation."Biochem Biphys Res Com. 269. 798-802 (2000)
[Publications] Hiraoka M: "Regulation of cardiac ion channels by phosphorylation, Ca^<2+>, cytoskeleton, and stretch."Heart Physiology and Pathophysiology. 389-406 (2001)
[Publications] Horie M: "Long QT syndrome as a cause of cardiac sudden death."Heart Failure, Frontiers in Cardiology. 105-113 (2000)
[Publications] Suketa Y: "Control and Disease of Sodium Dependent Transportation Proteins and Ion Channels"Elsevier, Amsterdam. (2000)
[Publications] Fukuda K: "Establishment of Cardiomyogenic Cell Line from Marrow Stroma. In Fourth International Symposium of Tissue Engineering for Therapetic Use 4."Elsevier. 55-66 (2000)

2000 Fiscal Year Annual Research Report

心臓血管系におけるチャネル病の発症と成因に関する調査・研究

Principal Investigator

平岡 昌和 東京医科歯科大学, 難治疾患研究所, 教授 (80014281)

Research Products

[Publications] Terai T: "Effects of external acidosis on HERG current expressed in Xenopusoocytes."J Mol Cell Cardiol. 32. 11-21 (2000)

[Publications] Nakajima T: "Characterization of S818L mutation in HERG C-terminus in LQT2. Modification on activation-deactivation gating properties."FEBS Leter. 481. 197-203 (2000)

[Publications] Moncada GA: "Effects of acidosis and NO on nicorandil-activated K_<ATP> channels in guinea-pig ventricular myocytes."Br J Pharmacol.. 131. 1097-1104 (2000)

[Publications] Akai J: "A novel SCN5A mutation associated with idiopathic ventricular fibrillation without typical ECG findings of Brugada syndrome."FEBS Letter. 479. 29-34 (2000)

[Publications] Hiraoka M: "Functional abnormalities of HERG channel mutations in LQT2."Jpn J Electrocardiol.. 20(Suppl3). 129-125 (2000)

[Publications] Makita N: "Cardiac Na^+ channel dysfunction in the Brugada syndrome is aggravated by β1 Subunit"Circulation. 101. 54-60 (2000)

[Publications] Wang DW: "Enhanced sodium channel intermediate inactivation in Brugada syndrome"Circulation Research. 87. E37-E43 (2000)

[Publications] Shimizu W: "Body surface distribution and response to drugs of ST segment elevation in the Brugada syndrome : Clinical implication of 87-leads body surface potential mapping and its application to 12-leads electrocardiograms."J Cardiovasc Electrophysiol. 11. 396-404 (2000)

[Publications] Yoshida H: "Characterization of a novel missense mutation in the pore region of HERG in a long QT syndrome."J Cardiovas Electrophysiol. 10. 1262-1270 (1999)

[Publications] Obayashi K: "On the mechanism of genistein-induced activation of protein kinase A-dependent Cl^- conductance in cardiac myocytes."Pflugers Archiv. 438. 269-277 (1999)

[Publications] Xie LH: "Phospholipase C-linked receptors regulate the ATP-sensitive potassium channel via depletion of phosphatidylinositol-4,5-biphosphate."Proc Natl Acad Sci USA. 96. 15292-15297 (1999)

[Publications] Horie M: "Blockade of cardiac ATP-sensitive K^+ channels by cibenzoline targets its pore-forming subunit."J Cardiovasc Pharmacol. 35. 434-422 (2000)

[Publications] Kono Y: "The properties of Kir6.1-6.2 tandem channel co-expressed with SUR2A."Pflugers Archiv Eur J Physiol. 440. 692-698 (2000)

[Publications] Haruna T: "Alteration of membrane lipid environment by 1-palmitoylcarnitine modulates K_<ATP> channels in guinea pig ventricular myocytes."Pflugers Archiv Eur J Physiol. 441. 200-207 (2000)

[Publications] Kubota T: "Hypokalemia-induced long QT syndrome with an underlying novel missense mutation in S4-S5 linker of KCNQ1."J Cardiovasc Electrophysiol. 11. 1048-54 (2000)

[Publications] Akao M: "Angiotensin II type 1 receptor blockade abolishes specific KATP channe gene exression in rats with myocardial infarction."J Mol Cell Cardiol. 32. 2239-2247 (2000)

[Publications] Yoshida H: "Bradycardia-induced long QT syndrome caused by a de novo missense mutation in the S2-S3 inner loop of HERG."Am J Human Genetics. 98. 348-352 (2001)

[Publications] Arimura T: "Characterization of human nebulette gene : A polymorphism in an actin-binding motif is associated with non-familial idiopathic dilated cardiomyopathy."Hum Genet. 107. 440-451 (2000)

[Publications] Lee WH: "Different expressivity of a ventricular essential light chain gene Ala57Gly mutation in familial hypertrophic cardiomyopathy."Am Heart J. (in press). (2001)

[Publications] Arimura T: "Identification, characterization and functional analysis of heart-specific myosin light chain phosphatase small subunit."J Biol Chem. (in press). (2001)

[Publications] Kimura A: "Molecular etiology of idiopathic cardiomyopathy in the Oriental populations."J Cardiol. (in press). (2001)

[Publications] Yamashita Y: "Two sporadic cases of Liddle syndrome caused by de novo ENaC mutations."Am J Kid Diseas. (2001)

[Publications] Date M: "Analysis on the -sarcoglycan Gene in Japanese Patients with Hypertrophic Cardiomyopathy."Am J Cardiol. 85. 1315-1318 (2000)

[Publications] Yamashita N: "The Involvement of Cytokines in the Mechanism of the Whole-body Hyperthermia-induced Cardioprotection"Circulation. 102. (2000)

[Publications] Hoshida S: "Cholesterol feeding exacerbates myocardial injury in Zucker diabetic fatty rats"Am J Physiol. 278. H256-H262 (2000)

[Publications] Sakata Y: "Calcineurin Inhibitor Attenuates Left Ventricular Hypertrophy, Leading to Prevention of Heart Failure in Hypertensive Rats."Circulation. 102. 2269-2275 (2000)

[Publications] Yamashita N: "The involvement of cytokines in the second window of ischemic preconditioning."Br J Pharmacol. (in press). (2001)

[Publications] Matsuoka,T: "C-Terminal tails of sulfonylurea receptors control ADP-induced activation and diazoxide modulation of ATP-sensitive K^+ channels."Circ.Res.. 87. 873-880 (2000)

[Publications] Fujita,S: "A regulator of G protein signalling (RGS) protein confers agonist-dependent relaxation gating to a G protein-gated K^+ channel."J Physiol. 526. 341-347 (2000)

[Publications] Tanemoto,M: "In vivo formation of a proton-sensitive K^+ channel by heteromeric subunit assembly of Kir5.1 with Kir4.1."J Physiol. 525. 587-592 (2000)

[Publications] Hibino,H: "Anchoring proteins confer G protein sensitivity to an inward-rectifier K^+ channel through the GK domain."EMBO J. 19. 78-83 (2000)

[Publications] Hazama A: "Swelling-activated, cystic fibrosis transmembrane conductance regulator-augmented ATP release and Cl^- conductances in C127 cells."J.Physiol.( London ). 523. 1-11 (2000)

[Publications] Morishima S: "Volume expansion sensitivity of swelling-activated Cl^- channel in human epithelial cells."Jpn J Physiol. 50. 277-280 (2000)

[Publications] Maeno E: "Normotonic cell shrinkage due to disordered volume regulation is an early prerequisite to apoptosis."Proc Natl Acad Sci USA. 97. 9487-9492 (2000)

[Publications] Shimizu S: "Ca^<2+>-sensing receptor-mediated regulation of volume-sensitive Cl^- channels in human epithelial cells."J.Physiol.(London). 528. 457-472 (2000)

[Publications] Yamashita T: "Short-term effects of rapid pacing on the mRNA levels of voltage-dependent K+ channels in the rat atrium : electrical remodeling in paroxysmal atrial tachycardia."Circulation. 101. 2007-2014 (2000)

[Publications] Kajimoto K: "Efficacy of continuous intravenous drip infusion of disopyramide in hypertrophic obstructive cardiomyopathy during cardiogenic shock."J Cardiol. 35. 197-203 (2000)

[Publications] Uzzaman M: "Remodeling of gap junctional coupling in hypertrophied right ventricles of rats with monocrotaline-induced pulmonay hypertension."Circ Res. 86. 871-878 (2000)

[Publications] Kodama I: "Gap junction remodeling in hypertrophied cardiac muscle."Jpn J Electrocardiology. 20(S3). 93-98 (2000)

[Publications] Emdad L: "Gap junction remodeling in hypertrophied left ventricles of aortic-banded rats : prevention by angiotensin II type 1 receptor blockade."J Mol Cell Cardiol. 33. 219-231 (2001)

[Publications] Kato T: "Calmodulin kinase-II, -IV and calcineurin are involved in leukemia inhibitory factor-induced cardiac hypertrophy in rats."Circ Res. 87. 937-945 (2000)

[Publications] Kodama H: "Significance of Raf-1/MEK/ERK cascade compared with JAK/STAT and PI3-K Pathway in gp130-mediated Cardiac Hypertrophy."Am J Physiol. 279. H1635-H1644 (2000)

[Publications] Fukuda K: "Cardiomyocyte Cell Line To Overcome Fibrotic Myocardium."Microcirculation annual. 16. 17-18 (2000)

[Publications] Sano M: "IL-6 Family of cytokines mediate angiotensin II-induced cardiac hypertrophy in rodent cardiomyocytes."J Biol Chem. 275. 29717-29723 (2000)

[Publications] Sano M: "Autocrine/Paracrine Secretion of IL-6 Family Cytokines Causes Angiotensin II-Induced Delayed STAT3 Activation."Biochem Biphys Res Com. 269. 798-802 (2000)

[Publications] Hiraoka M: "Regulation of cardiac ion channels by phosphorylation, Ca^<2+>, cytoskeleton, and stretch."Heart Physiology and Pathophysiology. 389-406 (2001)

[Publications] Horie M: "Long QT syndrome as a cause of cardiac sudden death."Heart Failure, Frontiers in Cardiology. 105-113 (2000)

[Publications] Suketa Y: "Control and Disease of Sodium Dependent Transportation Proteins and Ion Channels"Elsevier, Amsterdam. (2000)

[Publications] Fukuda K: "Establishment of Cardiomyogenic Cell Line from Marrow Stroma. In Fourth International Symposium of Tissue Engineering for Therapetic Use 4."Elsevier. 55-66 (2000)

平岡昌和東京医科歯科大学, 難治疾患研究所, 教授 (80014281)