1994 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	古川哲史東京医科歯科大学, 難治疾患研究所, 助手 (80251552) 松原弘明関西医科大学, 助手 (10239072) 永井良三東京大学, 医学部, 助教授 (60207975) 芹澤剛東京大学, 医学部, 講師 (90143429) 木村彰方九州大学, 生体防御医学研究所, 助教授 (60161551)
キーワード	肥大型心筋症 / 心筋βミオシン重鎖遺伝子 / ミオシン調節軽鎖遺伝子 / アイチン滑り速度 / QT延長症候群 / カリウムチャンネル遺伝子 / ナトリウムポンプ遺伝子 / ミトコンドリア心筋症
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。古賀は心筋βミオシン重鎖遺伝子変異と肥大型心筋症の病態を比較し、荷電変化を伴う変異例の心筋障害の進行が速いが、非ミオシン変異例でも同様な病態を示す例があり、未発見の遺伝子もザルコメア関連蛋白である可能性を示した。木村は18番染色体上に新たに同定したミオシン調節軽鎖遺伝子が心筋、骨格筋に強く発現し、そのプロモーターの多型性と肥大型心筋症が関連することを示した。芹澤は粘菌ミオシン重鎖遺伝子にヒト心筋症と同様な点変異を作成し、in vitro motility assayを用いて変異ミオシン上のアクチン滑り速度が低下することを示し、アクトミオシン相互作用の異常が心筋症の病因と関連することを明らかにした。家族性QT延長症候群については、長井は日本人13家系で11番染色体(11p15.5)に原因遺伝子を有する家系とそれ以外の遺伝子異常の家系が存在することを明らかにした。悪性不整脈との関連が推測される電位依存性K^+チャンネルについては、松原がKv1.5のクローニングを行ないその発現調節について検討した。その結果5'領域に存在するKREがKv1.5遺伝子非発現細胞では陰性調節配列として働き細胞特異的発現に重要であること、その作用にはDNA立体構造変化が関与する可能性を示した。Naポンプ遺伝子にはα_1、α_3アイソフォームが存在するが、古川は両アイソフォームを発現するBalb/c3T3細胞を作成した。その結果α_1とα_3は細胞外Naに対する親和性と電位依存性が異なり、この動態の差が特殊伝導系の自動能と関連する可能性が示した。杉山はミトコンドリア心筋症ではcomplex Iの減少、IIの増加を示し、、心筋線維の変性、骨格筋のragged-rad fiberと共に血管内皮の異常ミトコンドリアの増加と内径の狭小化を来すことを示した。

研究成果

(29件)

すべてその他

すべて文献書誌 (29件)

[文献書誌] Koga Y,et al: "Therapeutic management of dilated cardiomyopathy" Cardiovascular Drugs and Therapy. 8. 83-88 (1994)
[文献書誌] 古賀義則: "肥大型心筋症における心機能障害" 心臓. 26(Suppl2). 44-57 (1994)
[文献書誌] Nishi H,et al: "Possible gene dose effect of a mutant cardiac β-myosin heavy chain gene on the clinical manifestation of familial hypertrophic cardiomyopathy" Biochem Biophys Res Commun. 200. 549-556 (1994)
[文献書誌] Yamashita H,et al: "ADP inhibits sliding velocity of fluorescent actin filament on cardiac and skeletal myosins" Circulation Research. 74. 1027-1033 (1994)
[文献書誌] Sata M,et al: "A new in vitro motility assay technique to evaluate calcium sensitivity of the cardiac contractile proteins" Pflugers Arch. 429. 443-445 (1995)
[文献書誌] Kojima M,et al: "Angiotensin II receptor antagonist TCV 116 regresses hypertensive left ventricular hypertrophy in vivo and inhibits intracellular signaling pathway of stretch-mediated cardiomyocyte hypertrophy in vitro" Circulation. 89. 2204-2211 (1994)
[文献書誌] 松原弘明他4名: "Pretranslational mechanisms determine the type of potassium channels expressed in the rat skeletal and cardiac muscles" J.Biol.Chem.266. 13324-13328 (1991)
[文献書誌] T.Furukawa al.: "Mechanism for reactivation of the ATP-sensitive K+channel by MgATP complexes in guinea-pig ventricular myocytes" Journal of Physiology(London). 479.1. 95-107 (1994)
[文献書誌] T.Furukawa et al.: "Metabolic inhibition of l_<Ca,L> and l differs in feline left ventricular hypertrophy." American Journal of Physiology. 266. H1121-H1131 (1994)
[文献書誌] K.Ishibashi et al.: "Molecular cloning and expression of a member of the aquaporin family with permeability to glycerol and urea in addition to water expressed at the basolateral membrane of kidney collecting duct cells" Proceeding of National Academy of Science,USA. 91. 6269-6273 (1994)
[文献書誌] K.Fushimi al.: "Functional characterization and cell immunolocalization of AQP-CD water channel in kidney collecting duct" American Journal of Physiology. 267. F573-F582 (1994)
[文献書誌] J.Nitta et al.: "Subcellular mechanism for Ca^<2+>-dependent enhancement of delayed rectifier K^+ current in isolatedmembrane patches of guinea-pig ventricular myocytes." Circulation Research. 74. 96-104 (1994)
[文献書誌] Kurihara Y,et al.: "Disruption of mouse endothelin-1 gene results in lethality and craniofacial anomaly in homozygotes and elevated blood pressure in heterozygotes" Nature. 368. 703-710 (1994)
[文献書誌] Tanaka T,et al: "Gene linkage analysis of Romano-Ward syndrome (RWS) in 13 Japanese families" Human Genetics. 94. 380-384 (1994)
[文献書誌] Kuro-o M,et al: "Salt-sensitive hypertension in transgenic mice overexpressing sodium-proton exchanger" Circulation Research. 76. 148-153 (1995)
[文献書誌] 松原弘明他2名: "Regulatory mechanism for voltage-sensitive potassium channel gene in the heart" Jpn.J.Electrocardiology. 15. 25-33 (1995)
[文献書誌] 森泰清他4名: "The transcription of a mammalian voltage-gated potassium channel is regulated by cAMP in a cell-specific manner" J.Biol.Chem.268. 26482-26493 (1993)
[文献書誌] 松原弘明他5名: "Shaker-related potassium channel, Kv1.4, mRNA regulation in cultured rat heart myocytes and differential expression of Kv1.4 and Kv1.5 genes in myocardial development and hypertrophy." J Clin Invest. 92. 1659-1666 (1993)
[文献書誌] 古川哲史他: "左室圧負荷により発現するイオンチャネル" 心電図. 14. 32-41 (1994)
[文献書誌] Katsumata K,et al: "Fragmentation of human heart mitochodrial DNA associated with premature aging" Biochem Biophys Res Commun. 202. 102-110 (1994)
[文献書誌] Sato W,et al: "Cardiomyopathy and angiopathy in patients with mitochondrial myopathy, lactic acidosis and stroke-like episodes" American Heart Journal. 128. 733-741 (1994)
[文献書誌] Murakami T,et al: "Enzymatic and genetic adaptation of soleus muscle mitochondria to physical training in rats" American J Physiology(Endocri Metab). 267. E388-E395 (1994)
[文献書誌] Ozawa T,et al: "Mitochondrial DNA mutations and survival rate" Lancet. 345. 189 (1995)
[文献書誌] Nishi H,et al: "Cardiomyopathy Update 5 - Prognosis and Treatment of Cardiomyopathy and Myocarditis" University of Tokyo Press, 10 (1994)
[文献書誌] 西宏文他: "心臓病の分子医学-肥大型心筋症の遺伝子異常" 羊土社(矢崎義雄編), 10 (1994)
[文献書誌] Shiojima I,et al: "Diastolic Relaxation of the Heart" Kluwer Academic Publisher,Boston, 8 (1994)
[文献書誌] 杉山理: "ミトコンドリア遺伝子変異による心筋障害とは循環器 Now 6 心筋症・心筋炎" 南江堂(矢崎義雄、和泉徹編), 4 (1994)
[文献書誌] Kimura A,et al: "Developmental Mechanisms of Heart Disease" Futura Press, 8 (1995)
[文献書誌] Nagai R,et al: "The Adapted Heart" Raven Press, New York, 13 (1994)

1994 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: "Therapeutic management of dilated cardiomyopathy" Cardiovascular Drugs and Therapy. 8. 83-88 (1994)

[文献書誌] 古賀義則: "肥大型心筋症における心機能障害" 心臓. 26(Suppl2). 44-57 (1994)

[文献書誌] Nishi H,et al: "Possible gene dose effect of a mutant cardiac β-myosin heavy chain gene on the clinical manifestation of familial hypertrophic cardiomyopathy" Biochem Biophys Res Commun. 200. 549-556 (1994)

[文献書誌] Yamashita H,et al: "ADP inhibits sliding velocity of fluorescent actin filament on cardiac and skeletal myosins" Circulation Research. 74. 1027-1033 (1994)

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

[文献書誌] Kojima M,et al: "Angiotensin II receptor antagonist TCV 116 regresses hypertensive left ventricular hypertrophy in vivo and inhibits intracellular signaling pathway of stretch-mediated cardiomyocyte hypertrophy in vitro" Circulation. 89. 2204-2211 (1994)

[文献書誌] 松原弘明 他4名: "Pretranslational mechanisms determine the type of potassium channels expressed in the rat skeletal and cardiac muscles" J.Biol.Chem.266. 13324-13328 (1991)

[文献書誌] T.Furukawa al.: "Mechanism for reactivation of the ATP-sensitive K+channel by MgATP complexes in guinea-pig ventricular myocytes" Journal of Physiology(London). 479.1. 95-107 (1994)

[文献書誌] T.Furukawa et al.: "Metabolic inhibition of l_<Ca,L> and l differs in feline left ventricular hypertrophy." American Journal of Physiology. 266. H1121-H1131 (1994)

[文献書誌] K.Fushimi al.: "Functional characterization and cell immunolocalization of AQP-CD water channel in kidney collecting duct" American Journal of Physiology. 267. F573-F582 (1994)

[文献書誌] J.Nitta et al.: "Subcellular mechanism for Ca^<2+>-dependent enhancement of delayed rectifier K^+ current in isolatedmembrane patches of guinea-pig ventricular myocytes." Circulation Research. 74. 96-104 (1994)

[文献書誌] Kurihara Y,et al.: "Disruption of mouse endothelin-1 gene results in lethality and craniofacial anomaly in homozygotes and elevated blood pressure in heterozygotes" Nature. 368. 703-710 (1994)

[文献書誌] Tanaka T,et al: "Gene linkage analysis of Romano-Ward syndrome (RWS) in 13 Japanese families" Human Genetics. 94. 380-384 (1994)

[文献書誌] Kuro-o M,et al: "Salt-sensitive hypertension in transgenic mice overexpressing sodium-proton exchanger" Circulation Research. 76. 148-153 (1995)

[文献書誌] 松原弘明 他2名: "Regulatory mechanism for voltage-sensitive potassium channel gene in the heart" Jpn.J.Electrocardiology. 15. 25-33 (1995)

[文献書誌] 森 泰清 他4名: "The transcription of a mammalian voltage-gated potassium channel is regulated by cAMP in a cell-specific manner" J.Biol.Chem.268. 26482-26493 (1993)

[文献書誌] 松原弘明 他5名: "Shaker-related potassium channel, Kv1.4, mRNA regulation in cultured rat heart myocytes and differential expression of Kv1.4 and Kv1.5 genes in myocardial development and hypertrophy." J Clin Invest. 92. 1659-1666 (1993)

[文献書誌] 古川哲史 他: "左室圧負荷により発現するイオンチャネル" 心電図. 14. 32-41 (1994)

[文献書誌] Katsumata K,et al: "Fragmentation of human heart mitochodrial DNA associated with premature aging" Biochem Biophys Res Commun. 202. 102-110 (1994)

[文献書誌] Sato W,et al: "Cardiomyopathy and angiopathy in patients with mitochondrial myopathy, lactic acidosis and stroke-like episodes" American Heart Journal. 128. 733-741 (1994)

[文献書誌] Murakami T,et al: "Enzymatic and genetic adaptation of soleus muscle mitochondria to physical training in rats" American J Physiology(Endocri Metab). 267. E388-E395 (1994)

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

[文献書誌] Nishi H,et al: "Cardiomyopathy Update 5 - Prognosis and Treatment of Cardiomyopathy and Myocarditis" University of Tokyo Press, 10 (1994)

[文献書誌] 西 宏文 他: "心臓病の分子医学-肥大型心筋症の遺伝子異常" 羊土社(矢崎義雄 編), 10 (1994)

[文献書誌] Shiojima I,et al: "Diastolic Relaxation of the Heart" Kluwer Academic Publisher,Boston, 8 (1994)

[文献書誌] 杉山 理: "ミトコンドリア遺伝子変異による心筋障害とは 循環器 Now 6 心筋症・心筋炎" 南江堂(矢崎義雄、和泉 徹 編), 4 (1994)

[文献書誌] Kimura A,et al: "Developmental Mechanisms of Heart Disease" Futura Press, 8 (1995)

[文献書誌] Nagai R,et al: "The Adapted Heart" Raven Press, New York, 13 (1994)

1994 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] 松原弘明他4名: "Pretranslational mechanisms determine the type of potassium channels expressed in the rat skeletal and cardiac muscles" J.Biol.Chem.266. 13324-13328 (1991)

[文献書誌] 松原弘明他2名: "Regulatory mechanism for voltage-sensitive potassium channel gene in the heart" Jpn.J.Electrocardiology. 15. 25-33 (1995)

[文献書誌] 森泰清他4名: "The transcription of a mammalian voltage-gated potassium channel is regulated by cAMP in a cell-specific manner" J.Biol.Chem.268. 26482-26493 (1993)

[文献書誌] 松原弘明他5名: "Shaker-related potassium channel, Kv1.4, mRNA regulation in cultured rat heart myocytes and differential expression of Kv1.4 and Kv1.5 genes in myocardial development and hypertrophy." J Clin Invest. 92. 1659-1666 (1993)

[文献書誌] 古川哲史他: "左室圧負荷により発現するイオンチャネル" 心電図. 14. 32-41 (1994)

[文献書誌] 西宏文他: "心臓病の分子医学-肥大型心筋症の遺伝子異常" 羊土社(矢崎義雄編), 10 (1994)

[文献書誌] 杉山理: "ミトコンドリア遺伝子変異による心筋障害とは循環器 Now 6 心筋症・心筋炎" 南江堂(矢崎義雄、和泉徹編), 4 (1994)