Therapeutic application of vascular diseases by novel angiotensin II receptor signal regulating molecule

2005 Fiscal Year Final Research Report Summary

• Project/Area Number: 15390247
• 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: Ehime University
• Principal Investigator: HORIUCHI Masatsugu Ehime University, School of Medicine, Professor, 医学部, 教授 (40150338)
• Co-Investigator(Kenkyū-buntansha): IWAI Masaru Ehime University, School of Medicine, Associate professor, 医学部, 助教授 (00184854) ; MOGI Masaki Ehime University, School of Medicine, Lecturer, 医学部, 講師 (20363236)
• Project Period (FY): 2003 – 2005
• Keywords: Angiotensin / AT2 receptor / Vascular injury / Signal transduction / Oxidative stress / Cell proliferation / Transgenic mouse

Research Abstract

The cardiovascular actions of angiotensin II (Ang II) are mainly mediated by the Ang II type 1 (AT_1) receptor. We cloned a novel AT_1 receptor-associated protein (ATRAP) using a yeast two-hybrid screening system. To explore the role of ATRAP in vascular remodeling, we developed transgenic mice for mouse ATRAP-cDNA, and examined remodeling after inflammatory vascular injury induced by polyethylene-cuff placement. In ATRAP transgenic (ATRAP-Tg) mice, ATRAP mRNA was increased 3- to 4-fold in the heart, aorta and femoral artery. ATRAP-Tg mice showed no significant change in body weight, systolic blood pressure, heart rate and heart-to-body weight ratio. However, cell proliferation and neointimal formation in the injured artery were attenuated in ATRAP-Tg mice. The increase in NADPH oxidase activity and the expression of p22^<phox>, an NADH/NADPH oxidase subunit, after cuff placement was also attenuated in ATRAP-Tg mice. Moreover, activation of extracellular signal-regulated kinase (ERK), signal transducer and activator of transcription (STAT)1, and STAT3 after cuff placement were significantly reduced in ATRAP-Tg mice. In addition, we observed that cardiac hypertrophy induced by pressure-overload and Ang II infusion was attenuated in ATRAP-Tg mice, and that pressor response to Ang II was also decreased in ATRAP-Tg mice. These results suggest that ATRAP plays an important role in cardiovascular remodeling as a negative regulator.

Research Products

• [Journal Article] Interacting molecule of AT1 receptor, ATRAP, is colocalized with AT1 receptor in the mouse renal tubules. (2006)
  • Author(s): Tsurumi, Y., Tamura, K., Tanaka, Y., Koide, Y., Sakai, M., Yabana, M., et al.
  • Journal Title: Kidney Int 69 Pages: 488-494
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Interacting molecule of AT1 receptor, ATRAP, is colocalized with AT1 receptor in the mouse renal tubules. (2006)
  • Author(s): Tsurumi, Y., Tamura, K., Tanaka, Y., Koide, Y., Sakai, M., Yabana, M., Noda, Y., Hashimoto, T., Kihara, M,.Hirawa, N., Toya, Y., Kiuchi, Y., Iwai, M., Horiuchi, M., Umemura, S.
  • Journal Title: Kidney Int 69 Pages: 488-494
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The novel angiotensinII typel receptor(AT1R)-associated protein ATRAP downregulates AT1R and ameliorates cardiomyocyte hypertrophy. (2005)
  • Author(s): Tanaka, Y., Tamira, K., Koide, Y., Sakai, M., Tsurumi, Y., Noda, Y., et al.
  • Journal Title: FEBS Lett 579 Pages: 1579-1586
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Effect of azelnidipine on angiotensin II-mediated growth-promoting signaling in vascular smooth muscle cells. (2005)
  • Author(s): Li, J-M., Iwai, M., Cui, TX., Min, L-J., Tsuda, M., Iwanami, J., et al.
  • Journal Title: Mol Pharmacol 67 Pages: 1666-1673
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Inhibitory effects of AT1 receptor blocker, olmesartan, and estrogen on atherosclerosis via anti-oxidative stress. (2005)
  • Author(s): Tsuda, M., Iwai, M., Li, J-M., Li, H-S., Min, L-J., Ide, A., Okumura, M., et al.
  • Journal Title: Hypertension 45 Pages: 545-551
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The novel angiotensinII type1 receptor(AT1R)-associated protein ATRAP downregulates AT1R and ameliorates cardiomyocyte hypertrophy. (2005)
  • Author(s): Tanaka, Y., Tamura, K., koide, Y., Sakai, M., Tsurumi, Y., Noda, Y., et al.
  • Journal Title: FEBS Lett 597 Pages: 1570-1586
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Effect of combination of calcium channel blocker, azelnidipine, and AT1 receptor blocker, olmesartan, on atherosclerosis in apolipoprotein E-deficient mice. (2005)
  • Author(s): Suzuki, J., Iwai, M., Li, Z., Li, J-M., Min, LJ., Ide, A., Yoshii, T., et al.
  • Journal Title: J Hypertens 23 Pages: 1383-1389
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Deletion of angiotensin II type 2 receptor exaggerated atherosclerosis in apoE null mice. (2005)
  • Author(s): Iwai, M., Chen, R., Li, Z., Shiuchi, T., Suzuki, J., Ide, A., Tsuda, M., et al.
  • Journal Title: Circulation 112 Pages: 1636-1643
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Sex difference in vascular injury and vasoprotective effect of valsartan are related to differential AT_2 receptor expression. (2005)
  • Author(s): Okumura, M., Iwai, M., Ide, A., Nogi, M., Ito, M., Horiuchi,M.
  • Journal Title: Hypertension 46 Pages: 577-583
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Aldosterone and angiotensin II synergistically induce mitogenic response in vascular smooth muscle cells. (2005)
  • Author(s): Min, L-J., Mogi, M., Li, J-M., Iwanami, J., Iwai, M., Horiuchi,M.
  • Journal Title: Circ Res 97 Pages: 434-442
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The novel angiotensinII type1 receptor (AT1R) - associated protein ATRAP downregulates AT1R and ameliorates cardiomyocyte hypertrophy. (2005)
  • Author(s): Tanaka, Y., Tamura, K., Koide, Y., Sakai, M., Tsurumi, Y., Noda, Y., Umemura, M., Ishigami, T., Uchino, K., Horiuchi, M., Umemura, S.
  • Journal Title: FEBS Lett 579 Pages: 1579-1586
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effect of azelnidipine on angiotensin II-mediated growth-promoting signaling in vascular smooth muscle cells. (2005)
  • Author(s): Li, J-M., Iwai, M., Cui, TX., Min, L-J., Tsuda, M., Iwanami, J., Suzuki, J., Mogi, M., Horiuchi, M.
  • Journal Title: Mol Pharmacol 67 Pages: 1666-1673
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Inhibitory effects of AT1 receptor blocker, olmesartan, and estrogen on atherosclerosis via anti-oxidative stress. (2005)
  • Author(s): Tsuda, M., Iwai, M., Li, J-M., Li, H-S., Min, L-J., Ide, A., Okumura, M., Suzuki, J., Mogi, M., Suzuki, H., Horiuchi, M.
  • Journal Title: Hypertension 45 Pages: 545-551
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effect of combination of calcium channel blocker, azelnidipine, and AT1 receptor blocker, olmesartan, on atherosclerosis in apolipoprotein E-deficient mice. (2005)
  • Author(s): Suzuki, J., Iwai, M., Li, Z., Li, J-M., Min, LJ., Ide, A., Yoshii, T., Oshita, A., Mogi, M., Horiuchi, M.
  • Journal Title: J Hypertens 23 Pages: 1383-1389
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Deletion of angiotensin II type 2 receptor exaggerated atherosclerosis in apoE nul 1 mice. (2005)
  • Author(s): Iwai, M., Chen, R., Li, Z., Shiuchi, T., Suzuki, J., Ide, A., Tsuda, M., Okumura, M., Min, L-J., Mogi, M., Horiuchi, M.
  • Journal Title: Circulation 112 Pages: 1636-1643
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Sex difference in vascular injury and vasoprotective effect of valsartan are related to differential AT_2 receptor expression. (2005)
  • Author(s): Okumura, M., Iwai, M., Ide, A., Mogi, M., Ito, M., Horiuchi, M.
  • Journal Title: Hypertension 46 Pages: 577-583
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Aldosterone and angiotensin II synergistically induce mitogenic response in vascular smooth muscle cells. (2005)
  • Author(s): Min, L-J., Mogi, M., Li, J-M., Iwanami, J., Iwai, M., Horiuchi, M.
  • Journal Title: Circ Res 97 Pages: 434-442
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Regulation of collagen synthesis in mouse skin fibroblasts by distinct angiotensinII receptor subtypes. (2004)
  • Author(s): Min, L-J., Cui, T-X., Yahata, Y., Yamasaki, K., Shiuchi, T., et al.
  • Journal Title: Endocrinology 145 Pages: 253-260
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Nicotine enchances angiotensinII-induced mitogenic response in vascular smooth musele cells and fibroblasts. (2004)
  • Author(s): Li, J-M., Cui, T-X., Shiuchi, T., Liu, H-W., Min.L-J., et al.
  • Journal Title: Arterioscler Thromb Vasc Biol 24 Pages: 80-84
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Calcium channel blocker, azelnidipine, enhances vascular protective effects of ATI receptor blocker, olmesartan. (2004)
  • Author(s): Jinno, T., Iwai, M., Li, Z, Li, J-M., Liu, H-W., Cui, T-X., Rakugi, H., et al.
  • Journal Title: Hypertension 43 Pages: 263-269
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Regulation of IKB and MCP-1 by angiotensin type2 receptor-activated SHP-1 in fetal vascular smooth muscle cells. (2004)
  • Author(s): Wu, L., Iwai, M., Li, Z., Shiuchi, T., Min, L-J., Cui, T-X., Li, J-M., et al.
  • Journal Title: Mol Endocrinol 18 Pages: 666-678
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Possible inhibition of focal cerebral ischemia by angiotensinII type 2 receptor stimulation. (2004)
  • Author(s): Iwai, M., Liu, H-W., Chen, R., Ide, A., Okamoto, S., Hata, R., et al.
  • Journal Title: Circulation 110 Pages: 843-848
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Roles of AT1 and AT2 receptors in pregnancy-associated blood pressure change. (2004)
  • Author(s): Takeda-Matsubara, Y., Iwai, M., Cui, T-X., Shiuchi, T., Liu, H-W., et al.
  • Journal Title: Am J Hypertension 17 Pages: 684-689
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Trans-inactivation of receptor tyrosine kinases by novel angiotensinII AT2 receptor-interacting protein AT1P (2004)
  • Author(s): Nouet, S., Amzallag, N., Li, J-M., Louis, S., Seitz, I., Cui, T-X., et al.
  • Journal Title: J Bio1 Chem 279 Pages: 28989-28997
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] AngiotensinII type-1 receptor blocker valsartan enhances insulin sensitivity in skeletal muscles of deabetic mice. (2004)
  • Author(s): Shiuchi, T., Iwai, M., Li, H-S., Wu, L., Min, L-J, Li, J-M., Okumura, M., et sl.
  • Journal Title: Hypertension 43 Pages: 1003-1010
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Fluvastatin enhances the inhibitory effects of a selective AT1 receptor blocker,valsartan,on atherosclerosis. (2004)
  • Author(s): Li, Z., Iwai, M., Wu, L., Liu, H-W., Chen, R., Jinno, T., Suzuki, J., et al.
  • Journal Title: Hypertension 44 Pages: 758-763
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Nuclear receptor LXRalpha is involved in camp-mediated human rennin gene expression. (2004)
  • Author(s): Tamura, K., Chen, YE., Tanaka, Y., Sakai, M., Tsurumi, Y., et al.
  • Journal Title: Mol Cell Endocrinol 224 Pages: 11-20
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Regulation of collagen synthesis in mouse skin fibroblasts by distinct angiotensin II receptor subtypes. (2004)
  • Author(s): Min, L-J., Cui, T-X., Yahata, Y., Yamasaki, K., Shiuchi, T., Liu, H-W., Chen, R., Li, J-M., Okumura, M., Jinno, T., Wu, L., Iwai, M., Nahmias, C., Hashimoto, H., Horiuchi, M.
  • Journal Title: Endocrinology 145 Pages: 253-260
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Nicotine enhances angiotensinII-induced mitogenic response in vascular smooth muscle cells and fibroblasts. (2004)
  • Author(s): Li, J-M., Cui, T-X., Shiuchi, T., Liu, H-W., Min, L-J., Okumura, M., Jinno, T., Wu, L., Iwai, M., Horiuchi, M.
  • Journal Title: Arterioscler Thromb Vasc Biol 24 Pages: 80-84
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Calcium channel blocker, azelnidipine, enhances vascular protective effects of AT1 receptor blocker, olmesartan. (2004)
  • Author(s): Jinno, T., Iwai, M., Li, Z., Li, J-M., Liu, H-W., Cui, T-X., Rakugi, H., Ogihara, T., Horiuchi, M.
  • Journal Title: Hypertension 43 Pages: 263-269
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Regulation of IkB and MCP-1 by angiotensin type2 receptor-activated SHP-1 in fetal vascular smooth muscle cells. (2004)
  • Author(s): Wu, L., Iwai, M., Li, Z., Shiuchi, T., Min, L-J., Cui, T-X., Li, J-M., Okumura, M., Nahmias, C., Horiuchi, M.
  • Journal Title: Mol Endocrinol 18 Pages: 666-678
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Possible inhibition of focal cerebral ischemia by angiotensinII type 2 receptor stimulation. (2004)
  • Author(s): Iwai, M., Liu, H-W., Chen, R., Ide, A., Okamoto, S., Hata, R., Sakanaka, M., Shiuchi, T., Horiuchi, M.
  • Journal Title: Circulation 110 Pages: 843-848
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Roles of AT1 and AT2 receptors in pregnancy-associated blood pressure change. (2004)
  • Author(s): Takeda-Matsubara, Y., Iwai, M., Cui, T-X., Shiuchi, T., Liu, H-W., Okumura, M., Ito, M., Horiuchi, M.
  • Journal Title: Am J Hypertension 17 Pages: 684-689
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Trans-inactivation of receptor tyrosine kinases by novel angiotensinII AT2 receptor-interacting protein, ATIP (2004)
  • Author(s): Nouet, S., Amzallag, N., Li, J-M., Louis, S., Seitz, I., Cui, T-X., Alleaume, A-M., Di Bendetto, M., Boden, C., Masson, M., Strosberg, A-D., Horiuchi, M., Couraud, P-O., Nahmias, C.
  • Journal Title: J Biol Chem 279 Pages: 28989-28997
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] AngiotensinII type-1 receptor blocker valsartan enhances insulin sensitivity in skeletal muscles of diabetic mice. (2004)
  • Author(s): Shiuchi, T., Iwai, M., Li, H-S., Wu, L., Min, L-J., Li, J-M., Okumura, M., Cui, T-X., Horiuchi, M.
  • Journal Title: Hypertension 43 Pages: 1003-1010
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Fluvastatin enhances the inhibitory effects of a selective AT1 receptor blocker, valsartan, on atherosclerosis. (2004)
  • Author(s): Li, Z., Iwai, M., Wu, L., Liu, H-W., Chen, R., Jinno, T., Suzuki, J., Tsuda, M., Gao, X-Y., Okumura, M., Cui, T-X., Horiuchi, M.
  • Journal Title: Hypertension 44 Pages: 758-763
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Nuclear receptor LXRalpha is involved in camp-mediated human rennin gene expression. (2004)
  • Author(s): Tamura, K., Chen, YE., Tanaka, Y., Sakai, M., Tsurumi, Y., Koide, Y., Kihara, M., Pratt, RE., Horiuchi, M., Umemura, S., Dzau, VJ.
  • Journal Title: Mol Cell Endocrinol 224 Pages: 11-20
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Inhibition of experimental intimal thickening in mice lacking a novel G-Protein-coupled receptor. (2003)
  • Author(s): Tsukada, S., Iwai, M., Nishiu, J., Itoh, M., Tomoike, H., Horiuchi, M., et al.
  • Journal Title: Circulation 107 Pages: 313-319
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Role of At2 receptor in the brain in regulation of blood pressure and water intake. (2003)
  • Author(s): Li, Z., Iwai, M., Wu, L., Shiuchi, T., Jinno, T., Cui, T-X., Horiuchi,M.
  • Journal Title: Am J Physiol Heart Circ Physiol 284 Pages: 116-121
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Fluvastatin enhances the inhibitory effects of a selective AT1 receptor blocker valsartan on vascular neointimal formation. (2003)
  • Author(s): Horiuchi, M., Cui, T-X., Li, Z., Li, J-M., Nakagami, H., Iwai,M.
  • Journal Title: Circulation 107 Pages: 106-112
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cardioprotective role of AT2 receptor in post-infarction left ventricular remodeling (2003)
  • Author(s): Oishi, Y., Ozono, R., Yano, Y., Teranishi, Y., et al.
  • Journal Title: Hypertension 41 Pages: 814-818
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Angiotensin IItype 2 receptor deficiency exacerbates heart failure and reduces survival following acute myocardial infarction in mice. (2003)
  • Author(s): Adachi, Y., Saito, Y., Kishimoto, L., Harada, M., Kuwahara, K., et al.
  • Journal Title: Circulation 107 Pages: 2406-2408
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Important role of nitric oxide in the effect of angiotensin-converting enzyme inhibitor imidapril on vascular injury. (2003)
  • Author(s): Chen, R., Iwai, M., Wu, U., Suzuki, J., Min, L_J., Shiuchi, T., Sugaya, T., et al.
  • Journal Title: Hypertension 42 Pages: 542-547
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expression of endothelial angiotensinII receptor mRNA in pregnancy-induced hypertension. (2003)
  • Author(s): Takade-Matsubara, Y., Mathubara, K., Ochi, H., Ito, M., Iwai, M., et al.
  • Journal Title: Am J Hypertension 16 Pages: 993-999
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Inhibition of experimental intimal thickening in mice lacking a novel G-protein-coupled receptor. (2003)
  • Author(s): Tsukada, S., Iwai, M., Nishiu, J., Itoh, M., Tomoike, H., Horiuchi, M., Nakamura, Y., Tanaka, T.
  • Journal Title: Circulation 107 Pages: 313-319
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Role of AT2 receptor in the brain in regulation of blood pressure and water intake. (2003)
  • Author(s): Li, Z., Iwai, M., Wu, L., Shiuchi, T., Jinno, T., Cui, T-X., Horiuchi, M.
  • Journal Title: Am J Physiol Heart Circ Physiol 284 Pages: H116-H121
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Fluvastatin enhances the inhibitory effects of a selective AT1 receptor blocker valsartan on vascular neointimal formation. (2003)
  • Author(s): Horiuchi, M., Cui, T-X., Li, Z., Li, J-M., Nakagami, H., Iwai, M.
  • Journal Title: Circulation 107 Pages: 106-112
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cardioprotective role of AT2 receptor in post-infarction left ventricular remodeling. (2003)
  • Author(s): Oishi, Y., Ozono, R., Yano, Y., Teranishi, Y., Akishita, M., Horiuchi, M., Oshima, T., Kambe, M.
  • Journal Title: Hypertension 41 Pages: 814-818
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Agiotensin II type 2 receptor deficiency exacerbates heart failure and reduces survival following acute myocardial infarction in mice. (2003)
  • Author(s): Adachi, Y., Saito, Y., Kishimoto, I., Harada, M., Kuwahara, K., Takahashi, N., Kawakami, R., Nakanishi, M., Nakagawa, Y., Tanimoto, K., Saitoh, Y., Yasuno, S., Usami, S., Iwai, M., Horiuchi, M., Nakao, K.
  • Journal Title: Circulation 107 Pages: 2406-2408
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Important role of nitric oxide in the effect of angiotensin-converting enzyme inhibitor imidapril on vascular injury. (2003)
  • Author(s): Chen, R., Iwai, M., Wu, L., Suzuki, J., Min, L-J., Shiuchi, T., Sugaya, T., Liu, H-W., Cui, T-X., Horiuchi, M.
  • Journal Title: Hypertension 42 Pages: 542-547
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of endothelial angiotensinII receptor mRNA in pregnancy-induced hypertension. (2003)
  • Author(s): Takeda-Matsubara, Y., Matsubara, K., Ochi, H., Ito, M., Iwai, M., Horiuchi, M.
  • Journal Title: Am J Hypertension 16 Pages: 993-999
  • Description: 「研究成果報告書概要(欧文)」より