Research on mechanisms for vascular action of adrenomedullin

• Project/Area Number: 10218202
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: University of Tokyo
• Principal Investigator: HIRATA Yasunobu Univ. of Tokyo, Medicine, Associate Prof., 医学部附属病院, 講師 (70167609)
• Co-Investigator(Kenkyū-buntansha): SATA Masataka Univ. of Tokyo, Medicine, Lecturer, 医学部附属病院, 助手 (80345214) ; SUZUKI Etsu Univ. of Tokyo, Medicine, Lecturer, 医学部附属病院, 助手 (40313134)
• Project Period (FY): 1998 – 2002
• Project Status: Completed (Fiscal Year 2002)
• Budget Amount: ¥65,700,000 (Direct Cost: ¥65,700,000); Fiscal Year 2002: ¥12,600,000 (Direct Cost: ¥12,600,000); Fiscal Year 2001: ¥12,600,000 (Direct Cost: ¥12,600,000); Fiscal Year 2000: ¥13,500,000 (Direct Cost: ¥13,500,000); Fiscal Year 1999: ¥13,500,000 (Direct Cost: ¥13,500,000); Fiscal Year 1998: ¥13,500,000 (Direct Cost: ¥13,500,000)
• Keywords: adrenomedullin / nitric oxide / endothelium / PI3-K / Akt / vasodilation / knockout mice / ischemia / 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

Research Abstract

Adrenomedullin is a vasodilatory peptide and major source of circulating adrenomedullin is the vascular wall. The vascular action of adrenomedullin was at first considered to solely due elevated cAMP production, I. e., endothelium-independent vasodilation. However, we found that endothelial denudation substantially reduced the vasodilatory action of adrenomedullin in rodent aortic rings. Furthermore, this adrenomedullin-induced endothelium-dependent vasorelaxation is exerted mostly through activation of the phosphatydil inositol 3-kinase (PI3-K)/Akt pathway. It has been well established that this pathway is involved in various important actions such as anti-apoptosis and tissue protection as well as activation of endothelial nitric oxide synthase (eNOS).
Furthermore, we have reported that expression of the adrenomedullin gene is upregulated by hypoxia. Adrenomedullin abrogates ischemia/reperfusion renal injury. Studies using adrenomedullin gene knockout mice revealed that adrenomedullin plays an important role in vascular formation in embryos. Adrenomedullin transgenic mice were resistant to ischemia/reperfusion renal injury and adrenomedullin knockout mice vice versa. These findings suggest that endogenous adrenomedullin may play an important role as a tissue survival factor.

Research Products

• [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)
  • Description: 「研究成果報告書概要(和文)」より
• [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)
  • Description: 「研究成果報告書概要(和文)」より
• [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)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] 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)
  • Description: 「研究成果報告書概要(和文)」より
• [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 Vase Biol. 22. 1305-1309 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Nishimatsu H, Hirata Y et al.: "Endothelial responses of the aorta from adrenomedullin transgenic mice and knockout mice"Hypertens Res. 26. S79-S84 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] 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)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] 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)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] 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)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] 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)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] 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)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] 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)
  • 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] 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)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] 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)
• [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] Nishimatsu H, Hirata Y et al.: "Endothelial responses of the aorta from adrenomedullin transgenic mice and knockout mice"Hypertens Res. 26. S79-S84 (2003)
• [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"FASEB J. 15. 2530-2532 (2001)
• [Publications] Nishimatsu H, Hirata Y et al.: "Effects of intracavernous administration of adrenomedullin on erectile function in rats"Peptides. 22. 1913-1918 (2001)
• [Publications] 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)
• [Publications] Saiura A, Hirata Y et al.: "Circulating smooth muscle progenitor cells contribute to atherosclerosis"Nature Med. 7. 382-383 (2001)
• [Publications] Shindo T, Hirata Y et al.: "Vascular abnormalities and elevated blood pressure in mice lacking adrenomedullin gene"Circulation. 104. 1964-1971 (2001)
• [Publications] Oh-hashi Y, Hirata Y et al.: "Elevated Sympathetic Nervous Activity in Mice Deficient in CGRP"Circ Res. 89. 983-990 (2001)
• [Publications] 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)
• [Publications] 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)
• [Publications] Hirata Y, et al.: "Hypertension, diabetes mellitus, hypercholesterolemia, and endothelin B receptor-mediated renal nitric oxide release-Response."Circulation. 101. e228-e229 (2000)
• [Publications] 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)
• [Publications] 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)
• [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] 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)
• [Publications] Kakoki M, Hirata Y: "Effects of vasodilatory β-adrenoceptor antagonists on endothelium-derived nitric oxide release in rat kidney"Hypertension. 33. 467-471 (1999)
• [Publications] Hayakawa H, Hirata Y: "Role of nitric oxide-cGMP pathway in adrenomedullin-induced vasodilation in rat"Hypertension. 33. 689-693 (1999)
• [Publications] 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)
• [Publications] Nagata D, Hirata Y: "Hypoxia-induced adrenomedullin production in the kidney"Kidney Int. 55. 1259-1267 (1999)
• [Publications] Sata M, Hirata Y: "Adrenomedullin and nitric oxide inhibit human endothelial cell apoptosis via a cGMP-independent mechanism"Hypertension. (in press).
• [Publications] 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)
• [Publications] Kakoki M, Hirata Y: "Effects of vasodilatory β-adrenoceptor antagonists on endothelium-derived nitric oxide release in rat kidney." Hypertension. 33. 467-471 (1999)
• [Publications] Hayakawa H, Hirata Y,: "Role of nitric oxide-cGMP Pathway in adrenomedullin-induced vasodilation in rat." Hypertension. 33. 689-693 (1999)
• [Publications] 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).
• [Publications] Nagata D, Hirata Y,: "Hypoxia-induced adrenomedullin production in the kidney" Kidney Int,. (in press).
• [Publications] Suzuki E, Hirata Y: "Molecular mechanisms of endothelin-induced cell cycle progression phosphatidylinositol 3-kinase at distinct points." Circ Res. (in press).