1995 年度実績報告書

心筋細胞の分化異常と病態形成

研究課題

研究課題/領域番号	06274105
研究機関	久留米大学
研究代表者	古賀義則久留米大学, 医学部, 助教授 (50080669)
研究分担者	古川哲央東京医科歯科大学, 難治疾患研究所, 助手 (80251552) 松原弘明関西医科大学, 医学部, 講師 (10239072) 永井良三群馬大学, 医学部, 教授 (60207975) 杉山理応用生化学研究所, 部長 (30111850) 堀久枝東京医科歯科大学, 難治疾患研究所, 助手 (80014190)
キーワード	肥大型心筋症 / 収縮蛋白遺伝子異常 / アクチン滑り速度 / QT延長症候群 / カリウムチャンネル遺伝子 / ミトコンドリア心筋症 / アポトーシス / チロシンキナーゼ
研究概要	本研究の目的は心筋に特異的に分化した機能蛋白の異常を臨床的に分析し、その分子機構の解明を行うことである。肥大型心筋症については古賀は心筋βミオシン重鎖変異とトロポニンT変異例の病態を比較し、トロポニンT変異例では心筋肥厚は強くないが収縮不全を伴う例が多く、より重症な心筋病変を有することを示した。堀は本症の原因遺伝子として心筋βヒオシン重鎖、トロポニンT、αトロポミオシンの他に心室型ミオシンアルカリ軽鎖、心室型ミオシン調節軽鎖およびトロポニンI変異例を新たに発見した。杉浦はヒト心筋症と同様な変異を有するミオシンを作成してATPase活性、アクチン滑り速度を測定し、変異ミオシンのモーター機能が障害されており、その程度は臨床像と相関することを示した。QT延長症候群については、長井は11番、7番染色体上のK^+チャンネル点変異例を各々3、5家系で発見し、本症は人種的多型性を示すことを明らかにした。電位依存性K^+チャンネル(Kv1.5)遺伝子については、松原は転写開始点より約200塩基上流に同遺伝子の陰性調節領域が存在し、細胞特異的発現を規定していることを示した。古川は伸展刺激活性化および過分極活性化C1-チャンネルの全塩基配列を決定し、伸展刺激応答領域はN端に存在し、胎児心、圧負荷心で良mRNAの発現が増大することを示した。ミトコンドリア心筋症については、杉山はアミノ酸置換を来す変異はcytochrome oxidaseのサブユニット遺伝子に集積していること、tRNA、rRNA遺伝子の点変異は予後不良であることを示した。心筋細胞のアポトーシスについては、松森はマウス急性心筋炎でアポトーシスの存在を認めた。本田はチロシンキナーゼLTKのトランスジェニックマウスを作成し、心筋細胞特異的なLTK蛋白質の活性化に伴ない心筋細胞が変性、脱落することを示し、本モデルが心筋細胞の維持機構とチロシンキナーゼ系の解析に有用であることを明らかにした。

研究成果

(42件)

すべてその他

すべて文献書誌 (42件)

[文献書誌] Koga Y, et al: "Disappearance of giant negative T waves in patients with the Japanese form of apical hypertrophy" J Am Coll Cardiol. 26. 1672-1678 (1995)
[文献書誌] Nishi H, et al: "A myosin missense mutation, not a null allele, cauyses familial hyperprophic cardiomyopathy" Circulation. 91. 2911-2915 (1995)
[文献書誌] Nishi H, et al: "DNA typing of HLA class II genes in Japanese patients with dilated cardiomyopathy" J Mol Cell Cardiol. 27. 2385-2392 (1995)
[文献書誌] 古賀義則他: "肥大型心筋症の遺伝子異常と病態・治療" 循環器専門医. 4. 5-14 (1996)
[文献書誌] Yamada H, et al: "Secretion of laminin α2 chain in cerebrospinal fluid" FEBS Letters. 376. 37-40 (1995)
[文献書誌] Sata M, et al: "A new in vitro motility assay technique to evaluate calcium aensitivity of the cardias contractile protein" Pflugers Arch. 429. 443-445 (1995)
[文献書誌] Sata M, et al: "MCI-154 increasres Ca2^+ sensitivity of reconstituted thin filament. A study using a novel in vitro motility assay technique" Circ Res. 76. 626-633 (1995)
[文献書誌] Sugiura S, et al: "Force-velosity relations of rat cardiac myosin isozymes sliding on agal cell actin cables in vitro" Biophy Biochim Acta. 1231. 69-75 (1995)
[文献書誌] Sata M, et al: "Pimobendan directly sensitizes reconstituted thin filament to slide on cardiac myosin" Eur J Pharmacol. 290. 55-59 (1995)
[文献書誌] Sata M, et al: "Phosphocreatinine shuttle provides optimal condition for mechanical interaction of cardiac actomyosin" Circulation. 93. 310-317 (1995)
[文献書誌] Kurihara Y, et al: "Aortic arch malformation and ventricular septal defect in mice deficient in endothelin-1" J Clin Invest. 96. 293-300 (1995)
[文献書誌] Takewaki S, et al: "Activation of Na^+-H^+ antiporter (NHE-1) gene expression during growth, hypertrophy and proliferation of the rabbit cardio-vascular system" J Mol Cell Cardiol. 27. 729-742 (1995)
[文献書誌] Okamoto E, et al: "Diversity of the synthetic-state smooth muscle cells ptoliferating in mechanically and hemodynamically injured arteries" Lab Invest. 74. 120-128 (1996)
[文献書誌] Mori Y, et al: "GH3 cell-specific expression of Kv 1.5 gene, Regulation by a silencer containing dinucleotide repititive element" J Biol Chem. 270. 27788-27796 (1995)
[文献書誌] Mori Y, et al: "The transcription of a mammalian voltage-gated potassium channel is regulated by cAMP in a cell-spesific manner" J Biol Chem. 268. 26482-26493 (1993)
[文献書誌] Matsubara H, et al: "Shaker-related potasium channel, Kv 1.4, mRNA regulation in cultured rat heart myocytes and differential expression of Kv 1.5 genes in myocardial development and hypertrophy" J Clin Invest. 92. 1659-1666 (1993)
[文献書誌] Matsubara H, et al: "Pretranslational mechanisms determine the type of potassium channels expressed in the rat skiletal and cardiac muscles" J Biol Chem. 266. 13324-13328 (1991)
[文献書誌] Furukawa T, et al: "Molecular cloning and characterization of a novel truncated form (CIC-2) of CIC-2 (CIC-2G) in rabbit heart" FEBS Letters. 375. 56-62 (1995)
[文献書誌] Furukawa T, et al: "Negative charges that share important elements of function in cloned cardiac K^+ channel (Kv 1.5)" Heart Vessels. Suppl 9. 14-16 (1995)
[文献書誌] Furukawa T, et al: "Functional linkage of the cardiac ATP-sensitive K^+ channel to the actin cytoskeleton" Pfluger Arch. in press. (1996)
[文献書誌] Yamane T, et al: "4-Aminopyridine block oa the noninactivating cloned K^+ channel Kv 1.5 expressed in Xenopus oocytes" Am J Physiol. 269. H556-H564 (1995)
[文献書誌] 古川哲史: "肥大心筋におけるK^+チャネル変調-電気生理学的検討-" 心電図. 15. S-2-38-S-2-53 (1995)
[文献書誌] 平岡昌和、沢登徹、古川哲史: "虚血病態におけるATP感受性Kチャネルの開口の役割" Japancsc Circulation Journal. 58. 1225-1231 (1995)
[文献書誌] Ozawa T, et al: "Mitochondrial DNA mutations and survival rate" Lancet. 345. 189- (1995)
[文献書誌] Ozawa T, et al: "Genotype and phenotype of severe mitochondrial cardiomyopathy: a recipient of heart transplantation and the genetic control" Biochem Biophys Res Commun. 207. 613-620 (1995)
[文献書誌] Murakami T, et al: "Different adaptation to endurance training between heart and gastrocnemius muscle mitochondria in rats" Biochem Mol Biol Int. 36. 285-290 (1995)
[文献書誌] Sugiyama S, et al: "Preservation of mitochondrial respiratory function by coenzyme Q10 in aged rat skeletal muscle" Biochem Mol Biol Int. 37. 1111-1120 (1995)
[文献書誌] Hayakawa M, et al: "Mitochondrial DNA minicircles, lacking replication origins, exist in the cardiac muscle of a young normal subject" Biochem Biophys Res Comm. 215. 952-960 (1995)
[文献書誌] Yamada K, et al: "Early appearance of age-associated deterioration in mitochondrial function of diaphragm and heart in rats treated with doxorubicin" Exp Gerontol. 30. 581-593 (1995)
[文献書誌] Hirozane T, et al: "Experimental graft coronary artery disease in a murine heterotopic cardiac transplant model" Circulation. 91. 386-392 (1995)
[文献書誌] Sato M, et al: "Inotropic agent vesnarinone inhibits cytokine production and Eselectin expression in human umbilical vein endothelial cells" J Moll Cell Cardiol. 27. 2265-2273 (1995)
[文献書誌] Matsumori A, et al: "Dilated cardiomyopathy associated with hepatitis C virus infection" Circulation. 92. 2519-2525 (1995)
[文献書誌] Hirozane T, et al: "Beneficial effect of amrinone on murine cardiac allograft survial" Clin Exp Immunol. 102. 186-191 (1995)
[文献書誌] Furukawa Y, et al: "The angiotensin II receptor antagonist TCV-116 reduces graft coronary artery disease and preserves graft status in a murine model" Circulation. 93. 333-339 (1995)
[文献書誌] Watkins H, et al: "Mutations in the genes for cardiac troponin T and alphatropomyosin in hypertrophic cardiomyopathy" New Eng J Med. 332. 1058-1064 (1995)
[文献書誌] Honda H, et al: "Expression of p210bcr/abl by metallothionein promotor induced T- cell leukemia in transgenic mice" Blood. 85. 2853-2861 (1995)
[文献書誌] Honda H, et al: "Increasred tyrosine-phosphorylation of 55KDa proteins in β-actin/tec transgenic mice" Biochem Biophys Res Commun. 206. 287-293 (1995)
[文献書誌] Yamagata T, et al: "Of the GATA-binding proteins, only GATA4 selectively regulates human IL-5 promotor in IL-6 producing cells which express multiple GATA-binding proteins" Mol Cell Biol. 15. 3830-3839 (1995)
[文献書誌] 古賀義則他: "第24回日本医学会総会会誌(II)-肥大型心筋症診療の進歩" 第24回日本医学会総会, 2 (1995)
[文献書誌] Kimura A, et al: "Cardiac Development and Gene Regulation - Genetic approaches to identification of a novel gene responsible for familial hypertrophic cardiomyopathy" Excerpta Medica, 18 (1995)
[文献書誌] Sugiura S, et al: "Cardiac Energetics: From Emax to Pressure-Volume Area - Kinetic property of cardiac myosin in vitro" Kluwer Academic Publishers, 11 (1995)
[文献書誌] 杉山理: "第24回日本医学会総会会誌(I)-ミトコンドリア心筋症" 第24回日本医学会総会, 1 (1995)

1995 年度 実績報告書

心筋細胞の分化異常と病態形成

研究代表者

古賀 義則 久留米大学, 医学部, 助教授 (50080669)

研究成果

[文献書誌] Koga Y, et al: "Disappearance of giant negative T waves in patients with the Japanese form of apical hypertrophy" J Am Coll Cardiol. 26. 1672-1678 (1995)

[文献書誌] Nishi H, et al: "A myosin missense mutation, not a null allele, cauyses familial hyperprophic cardiomyopathy" Circulation. 91. 2911-2915 (1995)

[文献書誌] Nishi H, et al: "DNA typing of HLA class II genes in Japanese patients with dilated cardiomyopathy" J Mol Cell Cardiol. 27. 2385-2392 (1995)

[文献書誌] 古賀義則他: "肥大型心筋症の遺伝子異常と病態・治療" 循環器専門医. 4. 5-14 (1996)

[文献書誌] Yamada H, et al: "Secretion of laminin α2 chain in cerebrospinal fluid" FEBS Letters. 376. 37-40 (1995)

[文献書誌] Sata M, et al: "A new in vitro motility assay technique to evaluate calcium aensitivity of the cardias contractile protein" Pflugers Arch. 429. 443-445 (1995)

[文献書誌] Sata M, et al: "MCI-154 increasres Ca2^+ sensitivity of reconstituted thin filament. A study using a novel in vitro motility assay technique" Circ Res. 76. 626-633 (1995)

[文献書誌] Sugiura S, et al: "Force-velosity relations of rat cardiac myosin isozymes sliding on agal cell actin cables in vitro" Biophy Biochim Acta. 1231. 69-75 (1995)

[文献書誌] Sata M, et al: "Pimobendan directly sensitizes reconstituted thin filament to slide on cardiac myosin" Eur J Pharmacol. 290. 55-59 (1995)

[文献書誌] Sata M, et al: "Phosphocreatinine shuttle provides optimal condition for mechanical interaction of cardiac actomyosin" Circulation. 93. 310-317 (1995)

[文献書誌] Kurihara Y, et al: "Aortic arch malformation and ventricular septal defect in mice deficient in endothelin-1" J Clin Invest. 96. 293-300 (1995)

[文献書誌] Takewaki S, et al: "Activation of Na^+-H^+ antiporter (NHE-1) gene expression during growth, hypertrophy and proliferation of the rabbit cardio-vascular system" J Mol Cell Cardiol. 27. 729-742 (1995)

[文献書誌] Okamoto E, et al: "Diversity of the synthetic-state smooth muscle cells ptoliferating in mechanically and hemodynamically injured arteries" Lab Invest. 74. 120-128 (1996)

[文献書誌] Mori Y, et al: "GH3 cell-specific expression of Kv 1.5 gene, Regulation by a silencer containing dinucleotide repititive element" J Biol Chem. 270. 27788-27796 (1995)

[文献書誌] Mori Y, et al: "The transcription of a mammalian voltage-gated potassium channel is regulated by cAMP in a cell-spesific manner" J Biol Chem. 268. 26482-26493 (1993)

[文献書誌] Matsubara H, et al: "Shaker-related potasium channel, Kv 1.4, mRNA regulation in cultured rat heart myocytes and differential expression of Kv 1.5 genes in myocardial development and hypertrophy" J Clin Invest. 92. 1659-1666 (1993)

[文献書誌] Matsubara H, et al: "Pretranslational mechanisms determine the type of potassium channels expressed in the rat skiletal and cardiac muscles" J Biol Chem. 266. 13324-13328 (1991)

[文献書誌] Furukawa T, et al: "Molecular cloning and characterization of a novel truncated form (CIC-2) of CIC-2 (CIC-2G) in rabbit heart" FEBS Letters. 375. 56-62 (1995)

[文献書誌] Furukawa T, et al: "Negative charges that share important elements of function in cloned cardiac K^+ channel (Kv 1.5)" Heart Vessels. Suppl 9. 14-16 (1995)

[文献書誌] Furukawa T, et al: "Functional linkage of the cardiac ATP-sensitive K^+ channel to the actin cytoskeleton" Pfluger Arch. in press. (1996)

[文献書誌] Yamane T, et al: "4-Aminopyridine block oa the noninactivating cloned K^+ channel Kv 1.5 expressed in Xenopus oocytes" Am J Physiol. 269. H556-H564 (1995)

[文献書誌] 古川哲史: "肥大心筋におけるK^+チャネル変調-電気生理学的検討-" 心電図. 15. S-2-38-S-2-53 (1995)

[文献書誌] 平岡昌和、沢登徹、古川哲史: "虚血病態におけるATP感受性Kチャネルの開口の役割" Japancsc Circulation Journal. 58. 1225-1231 (1995)

[文献書誌] Ozawa T, et al: "Mitochondrial DNA mutations and survival rate" Lancet. 345. 189- (1995)

[文献書誌] Ozawa T, et al: "Genotype and phenotype of severe mitochondrial cardiomyopathy: a recipient of heart transplantation and the genetic control" Biochem Biophys Res Commun. 207. 613-620 (1995)

[文献書誌] Murakami T, et al: "Different adaptation to endurance training between heart and gastrocnemius muscle mitochondria in rats" Biochem Mol Biol Int. 36. 285-290 (1995)

[文献書誌] Sugiyama S, et al: "Preservation of mitochondrial respiratory function by coenzyme Q10 in aged rat skeletal muscle" Biochem Mol Biol Int. 37. 1111-1120 (1995)

[文献書誌] Hayakawa M, et al: "Mitochondrial DNA minicircles, lacking replication origins, exist in the cardiac muscle of a young normal subject" Biochem Biophys Res Comm. 215. 952-960 (1995)

[文献書誌] Yamada K, et al: "Early appearance of age-associated deterioration in mitochondrial function of diaphragm and heart in rats treated with doxorubicin" Exp Gerontol. 30. 581-593 (1995)

[文献書誌] Hirozane T, et al: "Experimental graft coronary artery disease in a murine heterotopic cardiac transplant model" Circulation. 91. 386-392 (1995)

[文献書誌] Sato M, et al: "Inotropic agent vesnarinone inhibits cytokine production and Eselectin expression in human umbilical vein endothelial cells" J Moll Cell Cardiol. 27. 2265-2273 (1995)

[文献書誌] Matsumori A, et al: "Dilated cardiomyopathy associated with hepatitis C virus infection" Circulation. 92. 2519-2525 (1995)

[文献書誌] Hirozane T, et al: "Beneficial effect of amrinone on murine cardiac allograft survial" Clin Exp Immunol. 102. 186-191 (1995)

[文献書誌] Furukawa Y, et al: "The angiotensin II receptor antagonist TCV-116 reduces graft coronary artery disease and preserves graft status in a murine model" Circulation. 93. 333-339 (1995)

[文献書誌] Watkins H, et al: "Mutations in the genes for cardiac troponin T and alphatropomyosin in hypertrophic cardiomyopathy" New Eng J Med. 332. 1058-1064 (1995)

[文献書誌] Honda H, et al: "Expression of p210bcr/abl by metallothionein promotor induced T- cell leukemia in transgenic mice" Blood. 85. 2853-2861 (1995)

[文献書誌] Honda H, et al: "Increasred tyrosine-phosphorylation of 55KDa proteins in β-actin/tec transgenic mice" Biochem Biophys Res Commun. 206. 287-293 (1995)

[文献書誌] Yamagata T, et al: "Of the GATA-binding proteins, only GATA4 selectively regulates human IL-5 promotor in IL-6 producing cells which express multiple GATA-binding proteins" Mol Cell Biol. 15. 3830-3839 (1995)

[文献書誌] 古賀義則他: "第24回日本医学会総会会誌(II)-肥大型心筋症診療の進歩" 第24回日本医学会総会, 2 (1995)

[文献書誌] Kimura A, et al: "Cardiac Development and Gene Regulation - Genetic approaches to identification of a novel gene responsible for familial hypertrophic cardiomyopathy" Excerpta Medica, 18 (1995)

[文献書誌] Sugiura S, et al: "Cardiac Energetics: From Emax to Pressure-Volume Area - Kinetic property of cardiac myosin in vitro" Kluwer Academic Publishers, 11 (1995)

[文献書誌] 杉山 理: "第24回日本医学会総会会誌(I)-ミトコンドリア心筋症" 第24回日本医学会総会, 1 (1995)

1995 年度実績報告書

古賀義則久留米大学, 医学部, 助教授 (50080669)

[文献書誌] 杉山理: "第24回日本医学会総会会誌(I)-ミトコンドリア心筋症" 第24回日本医学会総会, 1 (1995)