アドレノメデュリンの循環調節作用機序の解析

• 研究課題/領域番号: 10218202
• 研究種目: 特定領域研究
• 配分区分: 補助金
• 審査区分: 生物系
• 研究機関: 東京大学
• 研究代表者: 平田 恭信 東京大学, 医学部附属病院, 講師 (70167609)
• 研究分担者: 佐田 政隆 東京大学, 医学部附属病院, 助手 (80345214) ; 鈴木 越 東京大学, 医学部附属病院, 助手 (40313134)
• 研究期間 (年度): 1998 – 2002
• 研究課題ステータス: 完了 (2002年度)
• 配分額: 65,700千円 (直接経費: 65,700千円); 2002年度: 12,600千円 (直接経費: 12,600千円); 2001年度: 12,600千円 (直接経費: 12,600千円); 2000年度: 13,500千円 (直接経費: 13,500千円); 1999年度: 13,500千円 (直接経費: 13,500千円); 1998年度: 13,500千円 (直接経費: 13,500千円)
• キーワード: adrenomedullin / 動脈硬化 / NO / Akt / 血管内皮 / PI3-K / statin / Pl3-K / アドレノメデュリン / cGMP / cAMP / アポトーシス / 低酸素 / 遺伝子 / 尿細管 / 血管平滑筋細胞

研究概要

インスリン抵抗性状態では内皮機能障害が存在しこれが高血圧の発症あるいは維持に関わる可能性がある。しかしインスリン抵抗性状態で血管内皮機能が減弱する機序については不明な点が多い。高脂血症に広く用いられているstatin系薬剤やアドレノメデュリン(AM)はphosphatidylinositol-3 kinase(P-I-3K)/Akt案を介してNOを遊離させることが示されている。本研究ではインスリン抵抗性を示すZuckerラットにfluvastatinを投与してインスリンの作用ならびに内皮型NO合成酵素(eNOS)の活性化の両者に関与するP-I-3K/Akt系について解析した。16週齢Zucker肥満ラットのリング標本ではACh、AM投与による血管拡張は、対照群に比べ減弱していたが、statihの投与により対照群と同程度にまで改善した(%Δtension(10-6M ACh):対照-86±2,肥満-36±4,Statin-75±6%;P<0.05)。AMによる血管拡張はPI-3-K阻害薬であるLY294002(LY)前投与下で著明に減弱した。Western Blotによる検討ではAM 10-7M 15分刺激時のAktリン酸化は肥満群で低下していたが、Statin投与により約2倍に増加した。このAMによるAktのリン酸化はLY前投与により有意に抑制された。【結論】statin系薬剤はインスリン抵抗性ラットモデルにおいてAMによる血管拡張反応を改善した。またWestern blotでの検討結果からもstatinがP-I-3K/Akt経路を活性化していることが示唆された。StatinはAMと協調して内皮機能を改善させると考えられた。

研究成果

• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Shindo T, Hirata Y et al.: "Krappel-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)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Sata M, Hirata Y et al.: "Mouse genetic evidence that tranilast reduces smooth muscle cell hyperplasia via a p21(WAF1)-dependent pathway"Arterioscler Thromb Vase Biol. 22. 1305-1309 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Nishimatsu H, Hirata Y et al.: "Endothelial responses of the aorta from adrenomedullin transgenic mice and knockout mice"Hypertens Res. 26. S79-S84 (2003)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Hayakawa H, Hirata Y, Kakoki M, Suzuki Y, Nishimatsu H, Nagata D, Suzuki E, Kikuchi K, Nagano T, Kangawa K, Matsuo H, Sugimoto T, Omata M: "Role of nitric oxide-cGMP pathway in adrenomedullin-induced vasodilation in rat"Hypertension. 33. 689-693 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Nagata D, Hirata Y, Suzuki E, Kakoki M, Hayakawa H, Goto A., Ishimitsu I, Minamino N, Ono Y, Kangawa K, Matsuo H, Omata M: "Hypoxia-induced adrenomedullin production in the kidney"Kidney Int. 55. 1259-1267 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Sata M, Kakoki M, Nagata D, Nishimatsu H, Suzuki E, Aoyagi T, Sugiura S, Kojima H, Nagano T, Kangawa K, Matsuo H, Omata M, Nagai R, Hirata Y: "Adrenomedullin and nitric oxide inhibit human endothelial cell apoptosis via a cGMP-independent mechanism"Hypertension. 36. 83-88 (2000)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Shindo T, Kurihara Y, Nishimatsu H, Moriyama N, Kakoki M, Watatani S, Wang Y, Ebihara A, Kuwaki T, Ju K-H, Minamino N, Kangawa K, Ishikawa T, Fukuda M, Kudou A, Akimoto Y, Kawakami H, Imai Y, Imai T, Morita H, Yazaki Y, Nagai R, Hirata Y, Kurihara H: "Vascular abnormalities and elevated blood pressure in mice lacking adrenomedullin gene"Circulation. 104. 1964-1971 (2001)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Nishimatsu H, Suzuki E, Nagata D, Moriyama N, Satonaka H, Walsh K, Sata M, Kangawa K, Matsuo H, Goto A, Kitamura T, Hirata Y: "Adrenomedullin induces endothelium-dependent vasorelaxation via the phosphatidylinositol 3 kinase/akt-dependent pathway in rat aorta"Circ Res. 89. 63-70 (2001)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Nishimatsu H, Hirata Y, Hayakawa H, Nagata D, Satonaka H, Suzuki E, Horie S, Takeuchi T, Ohta N, Homma Y, Minowada S, Nagai R, Kawabe K, Kitamura T: "Effects of intracavemous administration of adrenomedullin on erectile function in rats"Peptides. 22. 1913-1918 (2001)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Nishimatsu H, Hirata Y, Shindo T, Kurihara H, Suzuki E, Sata M, Satonaka H, Takeda R, Nagata D, Kakoki M, Hayakawa H, Kangawa K, Matsuo H, Kitamura T, Nagai R: "Endothelial responses of the aorta from adrenomedullin transgenic mice and knockout mice"Hypertens Res. 26. S79-S84 (2003)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Sata M, Hirata Y et al.: "Hematopoietic stem cells differentiate into vascular cells that particiate in the pathogenesis of atherosclerosis"Nature Med. 8. 403-409 (2002)
• [文献書誌] 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)
• [文献書誌] 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)
• [文献書誌] 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)
• [文献書誌] 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)
• [文献書誌] Nishimatsu H, Hirata Y et al.: "Endothelial responses of the aorta from adrenomedullin transgenic mice and knockout mice"Hypertens Res. 26. S79-S84 (2003)
• [文献書誌] 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"FASEB J. 15. 2530-2532 (2001)
• [文献書誌] Nishimatsu H, Hirata Y et al.: "Effects of intracavernous administration of adrenomedullin on erectile function in rats"Peptides. 22. 1913-1918 (2001)
• [文献書誌] Nishimatsu H, Hirata Y et al.: "Adrenomedullin Induces Endothelium-Dependent Vasorelaxation via the Phosphatidylinositol 3 Kinase/Akt-Dependent Pathway in Rat Aorta"Circ Res. 89. 63-70 (2001)
• [文献書誌] Saiura A, Hirata Y et al.: "Circulating smooth muscle progenitor cells contribute to atherosclerosis"Nature Med. 7. 382-383 (2001)
• [文献書誌] Shindo T, Hirata Y et al.: "Vascular abnormalities and elevated blood pressure in mice lacking adrenomedullin gene"Circulation. 104. 1964-1971 (2001)
• [文献書誌] Oh-hashi Y, Hirata Y et al.: "Elevated Sympathetic Nervous Activity in Mice Deficient in CGRP"Circ Res. 89. 983-990 (2001)
• [文献書誌] Sata M,Hirata Y, et al.: "Adrenomedullin and nitric oxide inhibit human endothelial cell apoptosis via a cGMP-independent mechanism."Hypertension. 36. 83-88 (2000)
• [文献書誌] Kakoki M,Hirata Y, et al.: "Effects of tetrahydrobiopterin on endothelial dysfunction in rats with ischemic acute renal failure."J Am Soc Nephrol. 11. 301-309 (2000)
• [文献書誌] Hirata Y, et al.: "Hypertension, diabetes mellitus, hypercholesterolemia, and endothelin B receptor-mediated renal nitric oxide release-Response."Circulation. 101. e228-e229 (2000)
• [文献書誌] Suzuki E,Hirata Y, et al.: "Reentry into the cell cycle of contact-inhibited vascular endothelial cells by a phosphatase inhibitor : possible involvement of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase."J Biol Chem. 275. 3637-3644 (2000)
• [文献書誌] Nagata D,Hirata Y, et al.: "Cyclin A downregulation and p21cip1 upregulation correlate with GATA-6-induced growth arrest in glomerular mesangial cells."Circ Res. 87. 699-704 (2000)
• [文献書誌] 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)
• [文献書誌] Matsumoto A, Hirata Y: "The effect of nitric oxide on gas exchange in patients with congestive heart failure"Ann Intern Med. 130. 40-44 (1999)
• [文献書誌] Kakoki M, Hirata Y: "Effects of vasodilatory β-adrenoceptor antagonists on endothelium-derived nitric oxide release in rat kidney"Hypertension. 33. 467-471 (1999)
• [文献書誌] Hayakawa H, Hirata Y: "Role of nitric oxide-cGMP pathway in adrenomedullin-induced vasodilation in rat"Hypertension. 33. 689-693 (1999)
• [文献書誌] Kakoki M, Hirata Y: "Effects of hypertension, diabetes mellitus and hypercholesterolemia on endothelin type B receptor-mediated nitric oxide release from rat kidney"Circulation. 99. 1242-1248 (1999)
• [文献書誌] Nagata D, Hirata Y: "Hypoxia-induced adrenomedullin production in the kidney"Kidney Int. 55. 1259-1267 (1999)
• [文献書誌] Sata M, Hirata Y: "Adrenomedullin and nitric oxide inhibit human endothelial cell apoptosis via a cGMP-independent mechanism"Hypertension. (in press).
• [文献書誌] Matsumoto A, Hirata Y: "The effect of nitric oxide on gas exchange in patients with congestive heart failure." Ann Intern Med. 130. 40-44 (1999)
• [文献書誌] Kakoki M, Hirata Y: "Effects of vasodilatory β-adrenoceptor antagonists on endothelium-derived nitric oxide release in rat kidney." Hypertension. 33. 467-471 (1999)
• [文献書誌] Hayakawa H, Hirata Y,: "Role of nitric oxide-cGMP Pathway in adrenomedullin-induced vasodilation in rat." Hypertension. 33. 689-693 (1999)
• [文献書誌] Kakoki M, Hirata Y,: "Effects of hypertension diabetes mellitus and hypercholesterolemia on endothelin type B receptor-mediated nitric oxide release from rat kidney." Circulation,. (in press).
• [文献書誌] Nagata D, Hirata Y,: "Hypoxia-induced adrenomedullin production in the kidney" Kidney Int,. (in press).
• [文献書誌] Suzuki E, Hirata Y: "Molecular mechanisms of endothelin-induced cell cycle progression phosphatidylinositol 3-kinase at distinct points." Circ Res. (in press).