一酸化窒素と循環器病：遺伝子改変動物から得られた新知見
一酸化窒素合成酵素（nitric oxide synthase：NOS）には，神経型NOS，誘導型NOS，内皮型NOSの3種類のアイソフォームが存在する．従来，生体内におけるNOS系の役割が，NOS阻害薬を用いて薬理学的に広く検討されてきた．しかし，NOS阻害薬はさまざまな非特異的作用を有するため，NOS系の真の役割は，いまだ十分に解明されていない．この点を検討するために，著者らは，NOS系完全欠損マウスを世界に先駆けて開発した．興味深いことに，このマウスには，高度の冠動脈硬化を伴う自然発症の急性心筋梗塞が認められた．さらに，このマウスには，代謝症候群，高脂血症，拡張期心不全の病態も見出された...
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| Published in | 日本臨床麻酔学会誌 Vol. 32; no. 7; pp. 835 - 841 |
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| Main Author | |
| Format | Journal Article |
| Language | Japanese |
| Published |
日本臨床麻酔学会
2012
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0285-4945 1349-9149 |
| DOI | 10.2199/jjsca.32.835 |
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| Abstract | 一酸化窒素合成酵素（nitric oxide synthase：NOS）には，神経型NOS，誘導型NOS，内皮型NOSの3種類のアイソフォームが存在する．従来，生体内におけるNOS系の役割が，NOS阻害薬を用いて薬理学的に広く検討されてきた．しかし，NOS阻害薬はさまざまな非特異的作用を有するため，NOS系の真の役割は，いまだ十分に解明されていない．この点を検討するために，著者らは，NOS系完全欠損マウスを世界に先駆けて開発した．興味深いことに，このマウスには，高度の冠動脈硬化を伴う自然発症の急性心筋梗塞が認められた．さらに，このマウスには，代謝症候群，高脂血症，拡張期心不全の病態も見出された．以上より，NOS系が多彩な循環器病の成因に重要な役割を果たしていることが示唆された． |
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| AbstractList | 一酸化窒素合成酵素（nitric oxide synthase：NOS）には，神経型NOS，誘導型NOS，内皮型NOSの3種類のアイソフォームが存在する．従来，生体内におけるNOS系の役割が，NOS阻害薬を用いて薬理学的に広く検討されてきた．しかし，NOS阻害薬はさまざまな非特異的作用を有するため，NOS系の真の役割は，いまだ十分に解明されていない．この点を検討するために，著者らは，NOS系完全欠損マウスを世界に先駆けて開発した．興味深いことに，このマウスには，高度の冠動脈硬化を伴う自然発症の急性心筋梗塞が認められた．さらに，このマウスには，代謝症候群，高脂血症，拡張期心不全の病態も見出された．以上より，NOS系が多彩な循環器病の成因に重要な役割を果たしていることが示唆された． [要旨] 一酸化窒素合成酵素(nitric oxide synthase : NOS)には, 神経型NOS, 誘導型NOS, 内皮型NOSの3種類のアイソフォームが存在する. 従来, 生体内におけるNOS系の役割が, NOS阻害薬を用いて薬理学的に広く検討されてきた. しかし, NOS阻害薬はさまざまな非特異的作用を有するため, NOS系の真の役割は, いまだ十分に解明されていない. この点を検討するために, 著者らは, NOS系完全欠損マウスを世界に先駆けて開発した. 興味深いことに, このマウスには, 高度の冠動脈硬化を伴う自然発症の急性心筋梗塞が認められた. さらに, このマウスには, 代謝症候群, 高脂血症, 拡張期心不全の病態も見出された. 以上より, NOS系が多彩な循環器病の成因に重要な役割を果たしていることが示唆された. 「はじめに」 一酸化窒素(nitric oxide : NO)は, ほとんどすべての組織および臓器において生成・遊離され, 生体の恒常性の維持に重要な役割を果たしている1)～4). |
| Author | 筒井, 正人 |
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| Copyright | 2012 日本臨床麻酔学会 |
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| References | 23) Shibata K, Yatera Y, Furuno Y, et al.: Spontaneous development of left ventricular hypertrophy and diastolic dysfunction in mice lacking all nitric oxide synthases. Circ J 74: 2681-2692, 2010 10) Tsutsui M, Onoue H, Iida Y, et al.: Adventitia-dependent relaxations of canine basilar arteries transduced with recombinant eNOS gene. Am J Physiol 276: H1846-H1852, 1999 1) Tsutsui M: Neuronal nitric oxide synthase as a novel anti-atherogenic factor. J Atheroscler Thromb 11: 41-48, 2004 6) Tsutsui M, Chen AFY, O'Brien T, et al.: Adventitial expression of recombinant eNOS gene restores NO production in arteries without endothelium. Arterioscler Thromb Vasc Biol 18: 1231-1241, 1998 3) Tsutsui M, Shimokawa H, Morishita T, et al.: Development of genetically engineered mice lacking all three nitric oxide synthases. J Pharmacol Sci 102: 147-154, 2006 9) The World Health Report 2002 - Reducing Risks, Promoting Healthy Life. World Health Organization, 2002 16) Suda O, Tsutsui M, Morishita T, et al.: Long-term treatment with N (omega)-nitro-L-arginine methyl ester causes arteriosclerotic coronary lesions in endothelial nitric oxide synthase-deficient mice. Circulation 106: 1729-1735, 2002 14) Nakata S, Tsutsui M, Shimokawa H, et al.: Vascular neuronal NO synthase is selectively upregulated by platelet-derived growth factor: involvement of the MEK/ERK pathway. Arterioscler Thromb Vasc Biol 25: 2502-2508, 2005 4) Tsutsui M, Shimokawa H, Otsuji Y, et al.: Nitric oxide synthases and cardiovascular diseases: insights from genetically modified mice. Circ J 73: 986-993, 2009 18) Morishita T, Tsutsui M, Shimokawa H, et al.: Nephrogenic diabetes insipidus in mice lacking all nitric oxide synthase isoforms. Proc Natl Acad Sci U S A 102: 10616-10621, 2005 11) Tsutsui M, Onoue H, Iida Y, et al.: Effects of recombinant eNOS gene expression on reactivity of small cerebral arteries. Am J Physiol Heart Circ Physiol 278: H420-H427, 2000 21) Ulrich M, Petre A, Youhnovski N, et al.: Post-translational tyrosine nitration of eosinophil granule toxins mediated by eosinophil peroxidase. J Biol Chem 283: 28629-28640, 2008 2) Tsutsui M, Nakata S, Shimokawa H, et al.: Spontaneous myocardial infarction and nitric oxide synthase. Trends Cardiovasc Med 18: 275-279, 2008 7) Tsutsui M, Milstien S, Katusic ZS: Effect of tetrahydrobiopterin on endothelial function in canine middle cerebral arteries. Circ Res 79: 336-342, 1996 8) Chen AFY, O'Brien T, Tsutsui M, et al.: Expression and function of recombinant endothelial nitric oxide synthase gene in canine basilar artery. Circ Res 80: 327-335, 1997 15) Nakata S, Tsutsui M, Shimokawa H, et al.: Statin treatment upregulates vascular neuronal nitric oxide synthase through Akt/NF-kappaB pathway. Arterioscler Thromb Vasc Biol 27: 92-98, 2007 12) Tsutsui M, Onoue H, Iida Y, et al.: B1 and B2 bradykinin receptors on adventitial fibroblasts of cerebral arteries are coupled to recombinant eNOS. Am J Physiol Heart Circ Physiol 278: H367-H372, 2000 17) Suda O, Tsutsui M, Morishita T, et al.: Asymmetric dimethylarginine produces vascular lesions in endothelial nitric oxide synthase-deficient mice: involvement of renin-angiotensin system and oxidative stress. Arterioscler Thromb Vasc Biol 24: 1682-1688, 2004 19) Nakata S, Tsutsui M, Shimokawa H, et al.: Spontaneous myocardial infarction in mice lacking all nitric oxide synthase isoforms. Circulation 117: 2211-2223, 2008 13) Morishita T, Tsutsui M, Shimokawa H, et al.: Vasculoprotective roles of neuronal nitric oxide synthase. FASEB J 16: 1994-1996, 2002 22) Yatera Y, Shibata K, Furuno Y, et al.: Severe dyslipidaemia, atherosclerosis, and sudden cardiac death in mice lacking all NO synthases fed a high-fat diet. Cardiovasc Res 87: 675-682, 2010 5) Chen AFY, Jiang SW, Crotty TB, et al.: Effects of in vivo adventitial expression of recombinant endothelial nitric oxide synthase gene in cerebral arteries. Proc Natl Acad Sci U S A 94: 12568-12573, 1997 20) Takaki A, Morikawa K, Tsutsui M, et al.: Crucial role of nitric oxide synthases system in endothelium-dependent hyperpolarization in mice. J Exp Med 205: 2053-2063, 2008 |
| References_xml | – reference: 15) Nakata S, Tsutsui M, Shimokawa H, et al.: Statin treatment upregulates vascular neuronal nitric oxide synthase through Akt/NF-kappaB pathway. Arterioscler Thromb Vasc Biol 27: 92-98, 2007 – reference: 12) Tsutsui M, Onoue H, Iida Y, et al.: B1 and B2 bradykinin receptors on adventitial fibroblasts of cerebral arteries are coupled to recombinant eNOS. Am J Physiol Heart Circ Physiol 278: H367-H372, 2000 – reference: 10) Tsutsui M, Onoue H, Iida Y, et al.: Adventitia-dependent relaxations of canine basilar arteries transduced with recombinant eNOS gene. Am J Physiol 276: H1846-H1852, 1999 – reference: 11) Tsutsui M, Onoue H, Iida Y, et al.: Effects of recombinant eNOS gene expression on reactivity of small cerebral arteries. Am J Physiol Heart Circ Physiol 278: H420-H427, 2000 – reference: 18) Morishita T, Tsutsui M, Shimokawa H, et al.: Nephrogenic diabetes insipidus in mice lacking all nitric oxide synthase isoforms. Proc Natl Acad Sci U S A 102: 10616-10621, 2005 – reference: 19) Nakata S, Tsutsui M, Shimokawa H, et al.: Spontaneous myocardial infarction in mice lacking all nitric oxide synthase isoforms. Circulation 117: 2211-2223, 2008 – reference: 21) Ulrich M, Petre A, Youhnovski N, et al.: Post-translational tyrosine nitration of eosinophil granule toxins mediated by eosinophil peroxidase. J Biol Chem 283: 28629-28640, 2008 – reference: 22) Yatera Y, Shibata K, Furuno Y, et al.: Severe dyslipidaemia, atherosclerosis, and sudden cardiac death in mice lacking all NO synthases fed a high-fat diet. Cardiovasc Res 87: 675-682, 2010 – reference: 2) Tsutsui M, Nakata S, Shimokawa H, et al.: Spontaneous myocardial infarction and nitric oxide synthase. Trends Cardiovasc Med 18: 275-279, 2008 – reference: 14) Nakata S, Tsutsui M, Shimokawa H, et al.: Vascular neuronal NO synthase is selectively upregulated by platelet-derived growth factor: involvement of the MEK/ERK pathway. Arterioscler Thromb Vasc Biol 25: 2502-2508, 2005 – reference: 1) Tsutsui M: Neuronal nitric oxide synthase as a novel anti-atherogenic factor. J Atheroscler Thromb 11: 41-48, 2004 – reference: 23) Shibata K, Yatera Y, Furuno Y, et al.: Spontaneous development of left ventricular hypertrophy and diastolic dysfunction in mice lacking all nitric oxide synthases. Circ J 74: 2681-2692, 2010 – reference: 6) Tsutsui M, Chen AFY, O'Brien T, et al.: Adventitial expression of recombinant eNOS gene restores NO production in arteries without endothelium. Arterioscler Thromb Vasc Biol 18: 1231-1241, 1998 – reference: 8) Chen AFY, O'Brien T, Tsutsui M, et al.: Expression and function of recombinant endothelial nitric oxide synthase gene in canine basilar artery. Circ Res 80: 327-335, 1997 – reference: 5) Chen AFY, Jiang SW, Crotty TB, et al.: Effects of in vivo adventitial expression of recombinant endothelial nitric oxide synthase gene in cerebral arteries. Proc Natl Acad Sci U S A 94: 12568-12573, 1997 – reference: 9) The World Health Report 2002 - Reducing Risks, Promoting Healthy Life. World Health Organization, 2002 – reference: 20) Takaki A, Morikawa K, Tsutsui M, et al.: Crucial role of nitric oxide synthases system in endothelium-dependent hyperpolarization in mice. J Exp Med 205: 2053-2063, 2008 – reference: 16) Suda O, Tsutsui M, Morishita T, et al.: Long-term treatment with N (omega)-nitro-L-arginine methyl ester causes arteriosclerotic coronary lesions in endothelial nitric oxide synthase-deficient mice. Circulation 106: 1729-1735, 2002 – reference: 3) Tsutsui M, Shimokawa H, Morishita T, et al.: Development of genetically engineered mice lacking all three nitric oxide synthases. J Pharmacol Sci 102: 147-154, 2006 – reference: 13) Morishita T, Tsutsui M, Shimokawa H, et al.: Vasculoprotective roles of neuronal nitric oxide synthase. FASEB J 16: 1994-1996, 2002 – reference: 17) Suda O, Tsutsui M, Morishita T, et al.: Asymmetric dimethylarginine produces vascular lesions in endothelial nitric oxide synthase-deficient mice: involvement of renin-angiotensin system and oxidative stress. Arterioscler Thromb Vasc Biol 24: 1682-1688, 2004 – reference: 4) Tsutsui M, Shimokawa H, Otsuji Y, et al.: Nitric oxide synthases and cardiovascular diseases: insights from genetically modified mice. Circ J 73: 986-993, 2009 – reference: 7) Tsutsui M, Milstien S, Katusic ZS: Effect of tetrahydrobiopterin on endothelial function in canine middle cerebral arteries. Circ Res 79: 336-342, 1996 |
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| Snippet | 一酸化窒素合成酵素（nitric oxide... [要旨] 一酸化窒素合成酵素(nitric oxide synthase : NOS)には, 神経型NOS, 誘導型NOS, 内皮型NOSの3種類のアイソフォームが存在する. 従来, 生体内におけるNOS系の役割が, NOS阻害薬を用いて薬理学的に広く検討されてきた. しかし,... |
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| SubjectTerms | 一酸化窒素 一酸化窒素合成酵素 循環器病 心筋梗塞 遺伝子改変マウス |
| Title | 一酸化窒素と循環器病：遺伝子改変動物から得られた新知見 |
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