1997 Fiscal Year Annual Research Report

新規血管虚血負荷装置の開発と新しい虚血シグナルの同定及び虚血血管再生遺伝子治療

Research Project

Project/Area Number	09877192
Research Institution	Kyoto University
Principal Investigator	伊藤裕京都大学, 医学研究科, 助手 (40252457)
Keywords	内皮細胞 / 虚血 / ずり応力 / 血管新生 / VEGF
Research Abstract	本研究は、新しい血管虚血負荷装置の開発と、それを用いた内皮細胞での虚血応答遺伝子発現プログラム(虚血応答遺伝子群及び新たな虚血応答エレメントの同定)を明らかにすることをその目的とする。本年度は、内皮細胞において虚血刺激によりその遺伝子発現が誘導されることが知られている血管新生因子VEGF(Vascular Endothelial Growth Factor)に注目し、その遺伝子発現のシグナル機構を低酸素チャンバー及び平行平板型ずり応力負荷装置を用い検討した。VEGFは、培養ヒト冠動脈由来内皮細胞において、2%酸素刺激によりその発現が亢進したが、その発現誘導は動脈硬化病変形成に重要である酸化LDL及びその主成分であるリゾフォスファチジルコリン(Lyso PC)によりmimicされた。しかしながら、ずり応力負荷そのものではVEGF発現に著明な変化は認められなかった。また、実際のヒト冠動脈動脈硬化病変において、病変の進展に伴って障害内皮細胞においてVEGF発現が亢進していることを免疫組織化学的に証明した。以上の結果は、虚血シグナルを考える上で、酸化LDLやLysoPCのシグナル伝達に関与するNF-κBやAP-1活性の重要性を示唆している。更に、内皮細胞にVEGFを作用させると、血管収縮、血管増殖に対し促進的に働くエンドセリンの分泌及び、マクロファージ等血球の内皮への接着、遊走を促進する接着因子VCAM-1やケモカインであるMCP-1の発現が抑制されることも明らかにした。従って、虚血による内皮細胞の変化を考える上で、虚血刺激そのものにより生ずる変化とともに、虚血により誘導されるVEGF等虚血応答内皮由来生理活性物質による作用も重要であることが考えられた。

Research Products
(17 results)

All Other

All Publications (17 results)

[Publications] J.Yamashita, et al.: "Opposite regulation of Gax homeobox expression by angiotensin II and C-type natriuretic peptide." Hypertension. 29. 381-387 (1997)
[Publications] T-H.Chun, et al.: "Shear stress augments expression of C-type natriuretic peptide and adrenomedullin." Hypertension. 29. 1296-1302 (1997)
[Publications] T.Ikeda, et al.: "The plasma levels of brain and atrial natriuretic peptides elevate in proportion to the left ventricular end-systolic wall stress in patients with aortic stenosis." Am.Heart J.133. 307-314 (1997)
[Publications] H.Itoh, et al.: "Impaired guanosine 3',5'-cyclin phosphate production in severe pregnancy-induced hypertension with high plasma levels of atrial and brain natriuretic pepitdes." Endocrine J.44. 389-393 (1997)
[Publications] K.Yoshimine, et al.: "Altered expression of atrial natriuretic peptide and contractile protein genes in hypertrophied ventricle of JVS mice with systemic carnitine deficiency." J.Mol.Cell Cardiol.29. 571-578 (1997)
[Publications] H.Itoh, et al.: "Significance of vascular natriuretic peptide system in vascular remodeling in humans and its application to gene therapy." Annals New York Academy of Sciences. 811. 533-541 (1997)
[Publications] M.Harada, et al.: "Significance of ventricular myocytes and nonmyocytes interaction during cardiocyte hypertrophy-Evidence for endothelin-1 as a paracrine hypertrophic facter from cardiac nonmyocytes." Circulation. 96. 3737-3744 (1997)
[Publications] K.Doi, et al.: "Adenovirus-mediated gene transfer of C-type natriuretic peptide causes G1 growth inhibition of cultured vascular smooth muscle cells." Biochem.Biophys.Res.Commun.239. 889-894 (1997)
[Publications] J.Matsuda, et al.: "Cloning of rat uncoupling protein-3 and uncoupling protein-2 cDNAs:their gene expression in rats fed high-fat diet." FEBS Letters. 418. 200-204 (1997)
[Publications] K.Doi, et al.: "Expression of natriuretic peptide system during embryonic stem cell vasculogenesis." Heart and Vessels. Suppl.12. 18-22 (1997)
[Publications] M.Harada, et al.: "Role of cardiac nonmyocytes in cyclic mechanical stretch-induced myocyte hypertrophy." Heart and Vessels. Suppl.12. 198-200 (1997)
[Publications] K.Masatsuge, et al.: "Physiologic shear stress suppresses endothelin-converting enzyme-1 expression in vascular endothelial cells." J.Cardiovasc.Pharmacol.31Suppl.1. S42-S45 (1998)
[Publications] T.Saito, et al.: "Oxidative stress suppresses the endothelial secretion of endothelin." J.Cardiovasc.Pharmacol.31Suppl.1. S45-S47 (1998)
[Publications] S.Suga, et al.: "Regulation of endothelial production of C-type natriuretic peptide by interaction between endothelial cells and macrophages." Endocrinology. (in press). (1998)
[Publications] M.Suda, et al.: "Skeletal overgrowth in transgenic mice that overexpress brain natriuretic peptide." Proc.Natl.Acad.Sci.U.S.A.(in press). (1998)
[Publications] Y.Numata, et al.: "An immunoradiometric assay kit for N-terminal fragment of proatrial natriuretic peptide(Pro ANP N-peptide)in human plasma as a useful clinical test for heart failure." Endocrinol.Metabol.(in press). (1998)
[Publications] H.Itoh, et al.ed.by W.K.Samson and E.R.Levin: "″Contemporary Endocrinology:Natriuretic Peptides in Health and Disease″" Humana Press Inc.,Totowa,NJ, (1997)

1997 Fiscal Year Annual Research Report

新規血管虚血負荷装置の開発と新しい虚血シグナルの同定及び虚血血管再生遺伝子治療

Principal Investigator

伊藤 裕 京都大学, 医学研究科, 助手 (40252457)

Research Products

[Publications] J.Yamashita, et al.: "Opposite regulation of Gax homeobox expression by angiotensin II and C-type natriuretic peptide." Hypertension. 29. 381-387 (1997)

[Publications] T-H.Chun, et al.: "Shear stress augments expression of C-type natriuretic peptide and adrenomedullin." Hypertension. 29. 1296-1302 (1997)

[Publications] T.Ikeda, et al.: "The plasma levels of brain and atrial natriuretic peptides elevate in proportion to the left ventricular end-systolic wall stress in patients with aortic stenosis." Am.Heart J.133. 307-314 (1997)

[Publications] H.Itoh, et al.: "Impaired guanosine 3',5'-cyclin phosphate production in severe pregnancy-induced hypertension with high plasma levels of atrial and brain natriuretic pepitdes." Endocrine J.44. 389-393 (1997)

[Publications] K.Yoshimine, et al.: "Altered expression of atrial natriuretic peptide and contractile protein genes in hypertrophied ventricle of JVS mice with systemic carnitine deficiency." J.Mol.Cell Cardiol.29. 571-578 (1997)

[Publications] H.Itoh, et al.: "Significance of vascular natriuretic peptide system in vascular remodeling in humans and its application to gene therapy." Annals New York Academy of Sciences. 811. 533-541 (1997)

[Publications] M.Harada, et al.: "Significance of ventricular myocytes and nonmyocytes interaction during cardiocyte hypertrophy-Evidence for endothelin-1 as a paracrine hypertrophic facter from cardiac nonmyocytes." Circulation. 96. 3737-3744 (1997)

[Publications] K.Doi, et al.: "Adenovirus-mediated gene transfer of C-type natriuretic peptide causes G1 growth inhibition of cultured vascular smooth muscle cells." Biochem.Biophys.Res.Commun.239. 889-894 (1997)

[Publications] J.Matsuda, et al.: "Cloning of rat uncoupling protein-3 and uncoupling protein-2 cDNAs:their gene expression in rats fed high-fat diet." FEBS Letters. 418. 200-204 (1997)

[Publications] K.Doi, et al.: "Expression of natriuretic peptide system during embryonic stem cell vasculogenesis." Heart and Vessels. Suppl.12. 18-22 (1997)

[Publications] M.Harada, et al.: "Role of cardiac nonmyocytes in cyclic mechanical stretch-induced myocyte hypertrophy." Heart and Vessels. Suppl.12. 198-200 (1997)

[Publications] K.Masatsuge, et al.: "Physiologic shear stress suppresses endothelin-converting enzyme-1 expression in vascular endothelial cells." J.Cardiovasc.Pharmacol.31Suppl.1. S42-S45 (1998)

[Publications] T.Saito, et al.: "Oxidative stress suppresses the endothelial secretion of endothelin." J.Cardiovasc.Pharmacol.31Suppl.1. S45-S47 (1998)

[Publications] S.Suga, et al.: "Regulation of endothelial production of C-type natriuretic peptide by interaction between endothelial cells and macrophages." Endocrinology. (in press). (1998)

[Publications] M.Suda, et al.: "Skeletal overgrowth in transgenic mice that overexpress brain natriuretic peptide." Proc.Natl.Acad.Sci.U.S.A.(in press). (1998)

[Publications] Y.Numata, et al.: "An immunoradiometric assay kit for N-terminal fragment of proatrial natriuretic peptide(Pro ANP N-peptide)in human plasma as a useful clinical test for heart failure." Endocrinol.Metabol.(in press). (1998)

[Publications] H.Itoh, et al.ed.by W.K.Samson and E.R.Levin: "″Contemporary Endocrinology:Natriuretic Peptides in Health and Disease″" Humana Press Inc.,Totowa,NJ, (1997)

伊藤裕京都大学, 医学研究科, 助手 (40252457)