Role of angiotensin II receptor subtypes on cardiovascular remodeling induced by aortic banding

• Project/Area Number: 14570669
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Ehime University
• Principal Investigator: IWAI Masaru Ehime University, School of Medicine, Associate Professor, 医学部, 助教授 (00184854)
• Co-Investigator(Kenkyū-buntansha): HORIUCHI Masatsugu Ehime University, School of Medicine, Professor, 医学部, 教授 (40150338)
• Project Period (FY): 2002 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥2,900,000 (Direct Cost: ¥2,900,000); Fiscal Year 2004: ¥700,000 (Direct Cost: ¥700,000); Fiscal Year 2003: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 2002: ¥1,300,000 (Direct Cost: ¥1,300,000)
• Keywords: angiotensin / receptor / cardiac hypertrophy / coronary artery / AT1 receptor blocker / fibrosis / signal transducer / phosphatase / アポトーシス / Aortic banding / アンジオテンシンII受容体 / AT2受容体欠損マウス / Aortic Banding / 心筋細胞

Research Abstract

The banding of abdominal portion of aorta induced cardiac hypertrophy accompanied with the increase in heart weight, cardiomyocyte size, coronary artery thickness and perivascular fibrosis of coronary artery. In AT2 receptor deficient (AT2KO) mice, the changes of cardiac muscle were similar to, but the changes of coronary artery were more exaggerated than in wild type (WT) mice. Valsartan, an AT 1 receptor blocker, significantly inhibited the heart weight and cardiomyocyte size both in WT and AT2KO mice. The coronary artery thickening and perivascular fibrosis were inhibited by valsartan in WT mice, but the inhibitory actions of valsartan were smaller in AT2KO mice. Apoptosis detected by TUNEL staining, single stand DNA and Hoechst33342, and Bax expression was increased in coronary artery and perivascular region. The apoptotic changes were decreased in AT2KO mice but increased by valsartan in WT mice. Fibroblasts isolated and cultured from neonatal mice skin showed an increase in collagen synthesis and TIMP-1 expression by angiotensin (Ang) II. These changes induced by Ang II were inhibited by valsartan but enhanced by AT2 antagonist, PD123319. Ang II inhibited the increase in collagen synthesis and TIMT-1 expression induced by IGF-1 in AT1KO mice. Transfection of dominant negative mutant of a tyrosine phsphatase, SHP-1, into fibroblast decreased the inhibitory actions of Ang II on collagen synthesis in AT1KO mice.
These resukts suggest that AT2 receptor stimulation counter acts on the effects of AT 1 receptor stimulation to inhibit the changes of coronary artery thickening and perivascular fibrosis observed in cardiac hypertrophy.

Research Products

• [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., et al.
  • Journal Title: Arterio Thromb and 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 AT1 receptor blocker, olmesartan. (2004)
  • Author(s): Jinno, T., Iwai, M., Li, Z., Li, J-M., Liu, H-W., Cui, T-X., 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 IκB 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., 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-X., 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] 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] 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., 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 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: Arterio Thromb and 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 type 2 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] 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] 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., et al.
  • Journal Title: Arterio Thromb and Vase Biol 24 Pages: 80-84
• [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
• [Journal Article] Calcium channel blocker, azelnidipine, enhances vascular protective effects of ATl 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
• [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., 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., et al.
  • Journal Title: Am J Physiol Heart Circ Physiol 284
  • 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., et al.
  • 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., Akishita, M., 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 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., 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, L., 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): Takeda-Matsubara, Y., Matsubara, 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
  • 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
  • NAID: 110002709780
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Angiotensin 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
• [Journal Article] Effect of angiotensinII type 1 receptor blockade on cardiac remodeling in angiotensinII type 2 receptor null mice. (2002)
  • Author(s): Wu, L., Iwai, M., Nakagami, H., Chen, R., Suzuki, J., Akishita, M., et al.
  • Journal Title: Arterioscler Thromb Vasc Biol 22 Pages: 49-54
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Tumor necrosis of factor-a inhibits growth factor-mediated cell proliferation through SHP-1 activation in endothelia cells. (2002)
  • Author(s): Nakagami, H., Cui, T-X., Iwai, M., Shiuchi, T., Takeda-Matsubara, Y., et al.
  • Journal Title: Arterioscler Thromb Vasc Biol 22 Pages: 238-242
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] AT2 receptor activation inhibits insulin-induced phosphoinositide 3-kinase and Akt, and induces apoptosis in PC12W cells. (2002)
  • Author(s): Cui, T-X., Nakagami, H., Nahmias, C., Shiuchi, T., Takeda-Matsubara, Y., et al.
  • Journal Title: Mol Endocrinol 16 Pages: 2113-2123
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Role of angiotensinII-regulated apoptosis via distinct AT1 and AT2 receptors in neointimal formation. (2002)
  • Author(s): Suzuki, J., Iwai, M., Nakagami, H., Wu, L., Chen, R., Sugaya, T., et al.
  • Journal Title: Circulation 106 Pages: 847-853
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Effect of estrogen and AT1 receptor blocker on neointima formation. (2002)
  • Author(s): Liu, H-W., Iwai, M., Takeda-Matsubara, Y., Wu, L., Li, J-M., et al.
  • Journal Title: Hypertension 40 Pages: 451-457
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Effect of angiotensinII type 1 receptor blockade on cardiac remodeling in angiotensin II type 2 receptor null mice. (2002)
  • Author(s): Wu, L., Iwai, M., Nakagami, H., Chen, R., Suzuki, J., Akishita, M., Gasparo, M., Horiuchi, M.
  • Journal Title: Arterioscler Thromb Vasc Biol 22 Pages: 49-54
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Tumor necrosis factor-a inhibits growth factor-mediated cell proliferation through SHP-1 activation in endothelia cells. (2002)
  • Author(s): Nakagami, H., Cui, T-X., Iwai, M., Shiuchi, T., Takeda-Matsubara, Y., Wu, L., Horiuchi, M.
  • Journal Title: Arterioscler Thromb Vasc Biol 22 Pages: 238-242
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] AT2 receptor activation inhibits insulin-induced phosphoinositide 3-kinase and Akt, and induces apoptosis in PC12W cells. (2002)
  • Author(s): Cui, T-X., Nakagami, H., Nahmias, C., Shiuchi, T., Takeda-Matsubara, Y., Li, J-M., Wu, L., Iwai, M., Horiuchi, M.
  • Journal Title: Mol Endocrinol 16 Pages: 2113-2123
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Role of angiotensinII-regulated aptosis via distinct AT1 and AT2 receptors in neointimal formation. (2002)
  • Author(s): Suzuki, J., Iwai, M., Nakagami, H., Wu, L., Chen, R., Sugaya, T., Hamada M., Hiwada, K., Horiuchi, M.
  • Journal Title: Circulation 106 Pages: 847-853
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effect of estrogen and AT1 receptor blocker on neointimal formation. (2002)
  • Author(s): Liu, H-W., Iwai, M., Takeda-Matsubara, Y., Wu, L., Li, J-M., Okumura, M., Cui, T-X., Horiuchi, M.
  • Journal Title: Hypertension 40 Pages: 451-457
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Tsukada, S., Iwai, M., Nishiu, J., Itoh, M., Tomoike, H., Horiuchi, M., et al.: "Inhibition of experimental intimal thickening in mice lacking a novel G-protein-coupled receptor."Circulation. 107. 313-319 (2003)
• [Publications] Li, Z., Iwai, M., Wu, L., Shiuchi, T., Jinno, T., Cui, T-X., Horiuchi, M., et al.: "Role of AT2 receptor in the brain in regulation of blood pressure and water intake."Am J Physiol. 284. 116-121 (2003)
• [Publications] Horiuchi, M., Cui, T-X., Li, Z., Li, J-M., Nakagami, H., Iwai, M., et al.: "Fluvastatin enhances the inhibitory effects of a selective AT1 receptor blocker valsartan on vascular neointimal formation."Circulation. 107. 106-112 (2003)
• [Publications] Adachi, Y., Saito, Y., Kishimoto, I., Harada, M., Iwai, M., et al.: "Angiotensin II type2 receptor deficiency exacerbates heart failure and reduces survival following acute myocardial infarction in mice."Circulation. 107. 2406-2408 (2003)
• [Publications] Chen, R., Iwai, M., Wu, L., Suzuki, J., Min, L-J., Horiuchi, M., et al.: "Important role of nitric oxide in the effect of angiotensin-converting enzyme inhibitor imidapril on vascular injury."Hypertension. 42. 542-547 (2003)
• [Publications] Takeda-Matsubara, Y., Matsubara, K., Ochi, H., Ito, M., Iwai, M., et al.: "Expression of endothelial angiotensinII receptor mRNA in pregnancy-induced hypertension."Am J Hypertension. 16. 993-999 (2003)
• [Publications] Min, L-J., Cui, T-X., Yahata, Y., Yamasaki, K., Iwai, M., et al.: "Regulation of collagen synthesis in mouse skin fibroblasts by distinct angiotensin II receptor subtypes."Endocrinology. 145. 253-260 (2004)
• [Publications] Li, J-M., Cui, T-X., Shiuchi, T., Liu, H-W., Min, L-J., Iwai, M., et al.: "Nicotine enhances angiotensinII-induced mitogenic response in vascular smooth muscle cells and fibroblasts."Arterio Thromb Vasc Biol. 24. 80-84 (2004)
• [Publications] Jinno, T., Iwai, M., Li, Z., Li, J-M., Liu, H-W., Horiuchi, M., et al.: "Calcium channel blocker, azelnidipine, enhances vascular protective effects of AT1 receptor blocker, olmesartan."Hypertension. 43. 263-269 (2004)
• [Publications] Wu, L., Iwai, M., Li, Z., Shiuchi, T., Min, L-J., Cui, T-X., Horiuchi, M., et al.: "Regulation of IkB and MCP-1by angiotensin type2 receptor-activated SHP-1 in fetal vascular smooth muscle cells."Mol Endocrinology. (in press). (2004)
• [Publications] Lan Wu, Masaru Iwai, Hironori Nakagami, Rui Chen, Jun Suzuki, Masahiro Akishita, Marc de Gasparo, Masatsugu Horiuchi: "Effect of AT1 receptor blockade on cardiac remodeling in AT2 receptor null mice."Arteriosclero Thromb Vascular Biol. 22. 49-54 (2002)
• [Publications] Jun Suzuki, Masaru Iwai, Hironori Nakagami, Lan Wu, Rui Chen, Takashi Sugawara, Maremori Hamada, Kunio Hiwada, Masatsugu Horiuchi: "Role of angiotensin IL-regulated apoptosis through distinct AT1 and AT2 receptors in neointimal formation."Circulation. 106. 847-853 (2002)