部位指向性SODによるneurovascular networkと血液循環制御機構の解析

1996 Fiscal Year Annual Research Report

• Project/Area Number: 08457054
• Research Category: Grant-in-Aid for Scientific Research (B)
• Research Institution: Osaka City University
• Principal Investigator: 井上 正康 大阪市立大学, 医学部, 教授 (80040278)
• Keywords: 分子設計 / SOD / 活性酸素 / 酸素毒性 / フリーラジカル / NO / 高血圧 / ショック

Research Abstract

脳心血管障害をはじめとする各種疾患に活性酸素の関与が示唆されているが、その実体は尚不明である。申請者は、長時間循環型のpH感応性SOD (SM-SOD)、血管内皮親和性SOD (HB-SOD)、および肝細胞指向性SOD (GAL-SOD, MAN-SOD)等を開発し、固体レベルで部位特異的にスーパーオキシドを代謝制御し、高血圧、脳虚血障害、脳浮腫、肝移植病態等に活性酸素が関与する事を明らかにしてきた。本研究は、HB-SOD、MAN-SOD、及び同様の指向性を有するNO合成酵素阻害剤を開発し、全身血圧を監視制御する分子機構を解明する事を目的とする。これらの部位特異的SODを用いて解析した結果、全身の抵抗性血管ではスーパーオキシドとNOが同時に産生され、両者のバランスにより血圧が制御されていること、両化合物の基質である分子状酸素の局所濃度がNOの生物機能を規定する極めて重要な因子であり、低酸素文圧下ではNOが極めて強い作用を発現すること、およびこの性質が虚血局所の抵抗性血管を選択的に弛緩させる分子機構であることが判明した。Mannoseレセプター含有細胞に特異的に集積するNAN-SODを用いて解析した結果、投与直後に血圧が完全消失し、数分以内に動物が死亡することが判明した。不活化MAN-SODは本作用を示さず、Mannose結合アルブミンはこれを拮抗阻害することから、各種疾患において悪玉視されてきたスーパーオキシドが正常動物の血圧がMannoseレセプター含有細胞周辺では哺乳類生存に不可欠な血圧維持分子として作用し、血液循環を統合制御していることを世界で初めて示した。孤束核や血液中枢にもNO神経が存在するが、現在、その生理的意義を解析中である。

Research Products

• [Publications] M. Yabuki, Y. Inai, T. Yoshioka et, al: "Oxygen-dependent fragmentation of cellular DNA by nitric oxide" Free Rad. Res.(in press). (1996)
• [Publications] S. Iha, K. Orita, T. Kanno et, al.: "Oxygen-dependent inhibition of neutrophil respiratory burst by nitric oxide." Free Radical Res.(1996)
• [Publications] Kawada, N., Inoue, M. and Decker et, al.: "Effect of endothelins on hepatic stellate cells" Hepatology. (in press). (1996)
• [Publications] S. Okada, Y. Takehara, M. Yabuki et, al.: "Nitric oxide, a physiological modulator of mitochondrial function" Physiol Chem. Physics. 28. 69-82 (1996)
• [Publications] N. Kawada, T. Kuroki, M. Uoya et, al.: "Smooth muscle alpha-actin expression in rat hepatic stellate cells is regulated by nitric oxide and cGMP production" Biochem. Biophys. Res. Commun. (in press). (1996)
• [Publications] N. Kawada, T. Kuroki, K. Kobayashi et, al.: "Expression of heat shock protein 47 in mouse liver" Cell Tissue Res. 284. 341-346 (1996)
• [Publications] N. Kawada, T. Kuroki, K. Kobayashi et, al.: "Inhibition of myofibroblastic transformation of rat hepatic stellete cells by methylxanthine and cAMP" Dig. Dis. Sci.41. 1022-1029 (1996)
• [Publications] Sato, EF., Yamaoka, K. Morishita, S et al: "Low dose X-ray irradiation induce stress proteins but not prevent gastric mucosal lesion" Physiol. Chem. Phys. & Med.28. 103-109 (1996)
• [Publications] Ikeda, K., Kubo, S., Sato, EF et al: "Mechanism that regulates nitric oxide production by lipopolysaccharide-stimulated rat kupffer cells" Physiol. Chem.Phys. & Med. 2(in press). (1996)
• [Publications] M. Yabuki, Y. Inai, T. Yoshioka et, al.: "Oxygen-dependent fragmentation of cellular DNA by nitric oxide" Free Rad. Res.(in press). (1996)
• [Publications] S. Iha, K. Orita, T. Kanno et, al.: "Oxygen-dependent inhibition of neutrophil respiratory burst by nitric oxide." Free Radical Res.(1996)
• [Publications] Kawada, N., Inoue, M. and Decker et. al.: "Effect of endothelins on hepatic stellate cells" Hepatology. (in press). (1996)
• [Publications] S. Okada, Y. Takehara, M. Yabuki et, al.: "Nitric oxide, a physiological modulator of mitochondrial function" Physiol. Chem. Physics. 28. 69-82 (1996)
• [Publications] N. Kawada, T. Kuroki, M. Uoya et, al.: "Smooth muscle alpha-actin expression in rat hepatic stellate cells is regulated by nitric oxide and cGMP production" Biochem. Biophys. Res. Commun. (in press). (1996)
• [Publications] N. Kawada, T. Kuroki, K. Kobayashi et, al.: "Expression of heat shock protein 47 in mouse liver" Cell Tissue Res. 284. 341-346 (1996)
• [Publications] N. Kawada, T. Kuroki, K. Kobayashi et, al.: "Inhibition of myofibroblastic transformation of rat hepatic stellete cells by methylxanthine and cAMP" Dig. Dis. Sci.41. 1022-1029 (1996)
• [Publications] Sato, EF., Yamaoka, K. Morishita, S et al: "Low dose X-ray irradiation induce stress proteins but not prevent gastric mucosal lesion" Physiol. Chem. Phys. & Med.28. 103-109 (1996)
• [Publications] Ikeda, K., Kubo, S., Sato, EF. et al: "Mechanism that regulates nitric oside production by lipopolysaccharide-stimulated rat kupffer cells" Physiol. Chem. Phys. & Med. 28 (in press). (1996)
• [Publications] Yamamasu, S., Sato, E. F., Ogita, S., and Inoue, M.: "Role of glutathione metabolism and apoptosis in the regression of liver hemopoiesis" Free Radic. Biol. Med.23 (in press). (1997)
• [Publications] Yu, H., Sato, E. F., Arakawa, T. Kobayashi, K., and Inoue, M.: "Protective action of lipopolysaccaride on stress-induced gastric mucosal injury." Digestion.(in press). (1997)
• [Publications] M. Inoue, K. Inoue, K. Utsumi: "Brain Physiology and Disorder" Academic Press, 474 (1996)
• [Publications] M. Inoue, M. Nishikawa, E Sato, K. Utsumi: "Biology of nitric oxide" Portland Press, 353 (1996)
• [Publications] Y. Minamiyama, Takemura, M. Inoue: "Biology of nitric oxide" Portland Press, 353 (1996)
• [Publications] S.Takemura, Y. Minamiyama, M. Inoue: "Biology of nitric oxide" Portland Press, 353 (1996)
• [Publications] M. Inoue: "Food and Free Radicals (in press)" Prenum Press (in press), (1996)
• [Publications] M. Inoue, Y. Minamiyama, S. Takemura: "Meth. Enzymol." Academic Press, 528 (1996)
• [Publications] E. Sato, M. Inoue, K. Utsumi: "Meth. Enzymol." Academic Press, 522 (1996)
• [Publications] N. Kawada, S. Takemura, Y. Minamiyama, M. Inoue: "J. Hep. Bil. Pancr. Surg." 550 (1996)
• [Publications] N. Kawada, T. Kuroki, M. Uoya, K. Kobayashi, M. Inoue: "Cells of the Hepatic Sinusoid" Kuppfer Cells foundations, 650 (1997)
• [Publications] M. Uoya, N. Kawada, H. Tsutui, T. Kuroki, et al: "Cells of the Hepatic Sinusoid" Kuppfer Cells foundations, 650 (1996)
• [Publications] K. Ikeda, N. Kawada, F. Sato K. Kaneda, M. Inoue: "Cells of the Hepatic Sinusoid" Kuppfer Cells foundations, 650 (1996)
• [Publications] 井上正康: "活性酸素と医食同源" 共立出版, 356 (1996)
• [Publications] 井上正康: "活性酸素とシグナル伝達" 講談社, 220 (1996)
• [Publications] 井上正康: "アポトーシスの分子機構と病態" メディカルトリビューン社, 126 (1996)