Role of apoptosis of vascular endothelial cells In atherosclerosis

• Project/Area Number: 13470141
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: The University of Tokyo
• Principal Investigator: HIRATA Yasunobu The University of Tokyo, Faculty of Medicine, Lecturer, 医学部附属病院, 講師 (70167609)
• Co-Investigator(Kenkyū-buntansha): SATA Masataka The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (80345214) ; SUZUKI Etsu The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (40313134)
• Project Period (FY): 2001 – 2003
• Project Status: Completed (Fiscal Year 2003)
• Budget Amount: ¥11,100,000 (Direct Cost: ¥11,100,000); Fiscal Year 2003: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 2002: ¥1,300,000 (Direct Cost: ¥1,300,000); Fiscal Year 2001: ¥8,900,000 (Direct Cost: ¥8,900,000)
• Keywords: calcineurin / arteriosclerosis / MCP-I / adenovirus / VSMC / macrophage / apoptosis / アンジオテンシンII / 細胞内シグナル / NFAT3 / calcineurin / MEF2A

Research Abstract

Although the role of the calcineurin-dependent pathway in the development of cardiac hypertrophy has been intensively studied little is known of its role in vascular inflammatory diseases such as atherosclerosis and restenosis after angioplasty. To help elucidate the role of calcineurin in vascular inflammation, we infected cultured vascular smooth muscle cells (VSMCs) with an adenovirus construct expressing a constitutively active mutant of calcineurin, and examined its effect on the expression of monocyte chemoattractant protein-1 (MCP-1). We also examined the role of calcineurin in vivo using a transluminal wire injury model of the rat femoral artery. Forced activation of calcineurin significantly increased the expression of MCP-1 both at the transcriptional and protein levels, Angiotensin II (Ang II) also significantly stimulated MCP-1 expression, and this increase was significantly inhibited by cyclosporin A (CyA). Constitutive activation of calcineurin stabilized MCP-1 mRNA without enhancing MCP-1 promoter activity. In accordance with the results, Ang II-induced increase of MCP-1 promoter activity was not suppressed by CyA. Ang II stabilized MCP-1 mRNA, and this effect of Ang II was diminished by CyA. CyA suppressed MCP-1 expression in the femoral artery after the transluminal mechanical injury. CyA also inhibited macrophage Infiltration and neointimal formation in the wire-injured femoral arteries. These results suggested that calcineurin mediates vascular inflammation via stimulation of MCP-1 expression in VSMCs and macrophage infiltration.

Research Products

• [Publications] Sata M, Sugawara S, Yoshizumi M, Ouchi Y, Hirata Y, Nagai R: "Acute and chronic smooth muscle cell apoptosis after mechanical vascular injury can occur independently of the fas-death pathway."Arterioscler Thromb Vasc Biol. 21. 1733-1737 (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Nishimatsu H, Hirata Y 他: "Role of endogenous adrenomedullin in the regulation of vascular tone and ischemic renal injury : studies on transgenic/knockout mice of adrenomedullin gene."Circ Res. 90. 657-663 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Sata M., Hirata Y 他: "Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis."Nat Med. 29. 403-409 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Suzuki E, Nishimatsu H, Satonaka H, Walsh K, Goto A, Omata M, Fujita T, Nagai R, Hirata Y: "Angiotensin II induces myocyte enhancer factor 2- and calcineurin/ nuclear factor of activated T cell-dependent transcriptional activation in vascular myocytes."Circ Res. 90. 1004-1011 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Shindo T, Manabe I, Maemura K, Sata M, Hirata Y, Kadowaki T, Nagai R, etc.: "Kruppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling."Nat Med. 8. 856-863 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Abe M, Sata M, Nishimatsu H, Nagata D, Suzuki E, Terauchi Y, Kadowaki T, Matsuo H, Hirata Y, Nagai R: "Adrenomedullin augments collateral development in response to acute ischemia."Biochem Biophys Res Commun. 306. 10-15 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Sata M, Tanaka K, Ishizaka N, Hirata Y, Nagai R: "Absence of p53 leads to accelerated neointimal hyperplasia after vascular injury."Arterioscler Thromb Vase Biol. 23. 1548-1552 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Tanaka K, Hirata Y 他: "Diverse contribution of bone marrow cells to neointimal hyperplasia after mechanical vascular injuries."Circ Res. 93. 783-790 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Satonaka H, Hirata Y 他: "Calcineurin promotes the expression of monocyte chemoattractant protein-1 in vascular myocytes and mediates vascular inflammation."Circ Res. (In press).
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Niu P, Hirata Y 他: "Protective Effects of Endogenous Adrenomedullin on Cardiac Hypertrophy, Fibrosis, and Renal Damage."Circulation. (In press).
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Sata M, Sugiura S, Yoshizumi M, Ouchi Y, Hirata Y, Nagai R: "Acute and chronic smooth muscle cell apoptosis after mechanical vascular Injury can occur independently of the fas-death pathway."Arterioscler Thromb Vasc Blob. 21. 1733-1737 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Nishimatsu H, Hirata Y, Shindo T, Kurihara H, Kakoki M, Nagata D, Hayakawa H, Satonaka H, Sata M, Tojo A, Suzuki E, Kangawa K, Matsuo H, Kitamura T, Nagai R: "Role of endogenous adrenomedullin in the regulation of vascular tone and ischemic renal injury : studies on transgenic/knockout mice of adrenomedullin gene."Circ Res. 90. 657-663 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Sata M, Saiura A, Kunisato A, Tojo A, Okada S, Tokuhisa T, Hirai H, Makuuchi M, Hirata Y, Nagai R: "Hematopoietic stem cells differentiate into vascular cells that participate In the pathogenesis of atherosclerosis."Nat Med. 8. 403-409 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Suzuki E, Nishimatsu H, Satonaka H, Walsh K, Goto A, Omata M, Fujita T, Nagai R, Hirata Y: "Angiotensin II induces myocyte enhancer factor 2-and calcineurin/nuclear factor of activated T cell-dependent transcriptional activation in vascular myocytes."Circ Res. 90. 1004-1011 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Shindo T, Manabe I, Fukushima Y, Tobe K, Aizawa K, Miyamoto S, Kawai-Kowase K, Moriyama N, Imai Y, Kawakami H, Nishimatsu H, Ishikawa T, Suzuki T, Morita H, Maemura K, Sofa M, Hirata Y, Komukai M, Kagechika H, Kadowaki T, Kurabayashi M, Nagai R: "Kruppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling."Nat Med. 8. 856-863 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Abe M, Sofa M, Nishimatsu H, Nagata D, Suzuki E, Terauchi Y, Kadowaki T, Minamino N, Kangawa K, Matsuo H, Hirata Y, Nagai R: "Adrenomedullin augments collateral development in response t o acute ischemia."Biochem Biophys Res Commun. 306. 10-15 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Sofa M, Tanaka K, Ishizaka N, Hirata Y, Nagai R: "Absence of p53 leads to accelerated neointimal hyperplasia after vascular Injury."arterioscler Thromb Vasc Biol. 23. 1548-1552 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Tanaka K, Sata M, Hirata Y, Nagai R: "Diverse contribution of bone marrow cells to neointimal hyperplasia after mechanical vascular injuries."Circ Res. 93. 783-790 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Satonaka H, Suzuki E, Nishimatsu H, Takeda R, Goto A, Fujita T, Nagai R, Hirata Y: "Calcineurin promotes the expression of monocyte chemoattractant protein-1 in vascular myocytes and mediates vascular inflammation."Circ Res. (in press).
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Niu P, Shindo T, Iwata H, Iimuro S, Takeda N, Zhang Y, Ebihara A, Suematsu Y, Kangawa K, Hirata Y, Nagai R: "Protective Effects of Endogenous Adrenomedullin on Cardiac Hypertrophy, Fibrosis, and renal Damage."Circulation. (in press).
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Satonaka H, Hirata Y 他: "Calcineurin promotes the expression of monocyte chemoattractant protein-1 in vascular myocytes and mediates vascular inflammation."Circ Res. (in press). (2004)
• [Publications] Tanaka K, Hirata Y 他: "Diverse contribution of bone marrow cells to neointimal hyperplasia after mechanical vascular injuries."Circ Res. 93. 783-790 (2003)
• [Publications] Sata, M, Hirata, Y 他: "Absence of p53 leads to accelerated neointimal hyperplasia after vascular injury."Arterioscler.Thromb.Vasc.Biol. 23. 1548-1552 (2003)
• [Publications] Nishimatsu H, Hirata Y 他: "Endothelial responses of the aorta from adrenomedullin transgenic mice and knockout mice."Hypertens Res. 26 Suppl. S79-S84 (2003)
• [Publications] Abe M, Hirata Y 他: "Adrenomedullin augments collateral development in response to acute ischemia."Biochem Biophys Res Commun. 306. 10-15 (2003)
• [Publications] Fukino K, Hirata Y 他: "Genetic background influences therapeutic effectiveness of VEGF."Biochem Biophys Res Commun. 310. 143-147 (2003)
• [Publications] Sata M, Hirata Y et al.: "Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis"Nature Med. 8. 403-409 (2002)
• [Publications] Suzuki E, Hirata Y et al.: "Angiotensin II induces myocyte enhancer factor 2-and calcineurin/nuclear factor of activated T cell-dependent transcriptional activation in vascular myocytes"Circ Res. 90. 1004-1011 (2002)
• [Publications] Nishimatsu H, Hirata Y et al.: "Role of endogenous adrenomedullin in the regulation of vascular tone and ischemic renal injury : studies on transgenic/knockout mice of adrenomedullin gene"Circ Res. 90. 657-663 (2002)
• [Publications] Shindo T, Hirata Y et al.: "Kruppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling"Nature Med. 8. 856-863 (2002)
• [Publications] Sata M, Hirata Y et al.: "Mouse genetic evidence that tranilast reduces smooth muscle cell hyperplasia via a p21(WAF1)-dependent pathway"Arterioscler Thromb Vasc Biol. 22. 1305-1309 (2002)
• [Publications] Suzuki N, Hirata Y et al.: "Orthogonality of calcium concentration and ability of 4,5-diaminofluorescein (DAF-2) to detect NO"J Biol Chem. 277. 47-49 (2002)
• [Publications] Sata M, Hirata Y, et al.: "Endothelial nitric oxide synthase is essential for the HMG-CoA reductase inhibitor cerivastatin to promote collateral growth in response to ischemia"FADEB J. 15. 2530-2532 (2001)
• [Publications] Nagata D, Hirata, Y et al.: "Transcriptional activation of the cyclin D1 gene is mediated by multiple cis elements including SP1 sites and a cyclic AMP responsive element in vascular endothelial cells"J Biol Chem. 276. 662-669 (2001)
• [Publications] Nishimatsu A, Hirata Y, et al.: "Adremomedullin Induces Endothelium-Dependent Vasorelaxation via the Phosphatidylinositol 3 Kinase/Akt-Dependent Pathway in Rat Aorta"Circ Res. 89. 63-70 (2001)
• [Publications] Saiura A, Hirata Y, et al.: "Circulating smooth muscle progenitor cells contribute to atherosclerosis"Nature Med. 7. 382-383 (2001)
• [Publications] Sata M, Hirata Y, et al.: "Acute and chronic smooth muscle cell apoptosis after mechanical vascular injury can occur independently of the fas-death pathway"Arterioscler Thromb Vasc Biol. 21. 1733-1737 (2001)
• [Publications] Hirata Y et al.: "Measurement of plasma brain natriuretic peptide level as a guide for cardiac overload"Carduiovasc Res. 51. 585-591 (2001)