Cross-talk between angiotensin II receptor and cytokines in vascular disease

2002 Fiscal Year Final Research Report Summary

• Project/Area Number: 12470156
• 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, Medicine, Professor, 医学部, 教授 (40150338)
• Co-Investigator(Kenkyū-buntansha): IWAI Masaru Ehime University, Medicine, Associate Professor, 医学部, 助教授 (00184854) ; HIWADA Kunio Ehime University, Medicine, Professor, 医学部, 教授 (00108391)
• Project Period (FY): 2000 – 2002
• Keywords: angioteasin / receptor / vascular remodeling / cytokine / transcription factor / gene-engineered mouse / vascular inflammation

Research Abstract

Neointimal formation and DNA synthesis in vascular smooth muscle cell (VSMC) after cuff placement in the femoral artery were exaggerated in AT2 receptor null mice, but suppressed in AT1a receptor null mice. The number of apoptotic cells in VSMC in the injured artery was significantly increased in AT1a receptor null mice, but decreased in AT2 receptor null mice. Moreover, cuff placement increased the expression of MCP-1, inflammatory cytokines such as TNF-a, IL-6, and IL-1b and infiltration of CD45-positive leukocytes and macrophage in the injured arteries and further enhanced in AT2 receptor null mice, suggesting the antagonistic effects of AT1 and AT2 receptors and vascular inflammation. We also demonstrated that AT2 receptor was expressed in human coronary atherosclerotic lesions. We have identified the interferon regulatory factor (IRF) binding motif in a negative regulatory region between positions -453 and -225, and demonstrated that the expression of AT2 receptor in these cells is transcriptionally regulated by the competitive binding of two related IRFs (IRF-1 and IRF-2) and demonstrated that that IFN-g upregulated AT2 receptor expression in R3T3 cells via the activation of the intracellular Jak/STAT pathway and production of IRF-1. To test the physiological relevance of the role of IRF-1 in vascular remodeling, we employed IRF-1 null mice and observed that AT2 receptor expression was low associated with increase in neointimal formation, increase in DNA synthesis in VSMC, and decrease in apoptotic changes in VSMC in the injured artery of IRF-1 null mice compared to those in wild type mice.

Research Products

• [Publications] Horiuchi, M., Hayashida, W., Akishita, M., Yamada, S., Lehtonen, J.Y.A., Tamura, K., Daviet, L., Y.E.Chen., Hamai, M., Cui, T-x., Iwai, M., Minokoshi, Y.: "Interferon-γ induced AT2 receptor expression in fibroblasts by Jak/STAT pathway and interferon regulatory factor-1"Circ Res. 86. 233-240 (2000)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Akishita, M., Horiuchi, M., Yamada, H., Zhang, L., Shirakami, G., Tamura, K., Ouchi, Y., Dzau, V.J.: "Inflammation influences vascular remodering through AT2 receptor expression and signaling"Physiol Genomics. 2. 13-30 (2000)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Akishita, M., Iwai, M., Lan, W., Zhang, L., Ouchi, Y., Dzau, V.J., Horiuchi, M.: "Inhibitory effect of AT2 receptor on coronary arterial remodeling after aortic banding in mice"Circulation. 102. 1684-1689 (2000)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Wu, L., Iwai, M., Nakagami, H., Li, M., Chen, R., Suzuki, J., Akishita, M., de Gasparo, M., Horiuchi, M.: "Roles of AT2 receptor stimulation associated with selective AT1 receptor blockade with valsartan in the improvement of inflammation-induced vascular injury"Circulation. 104. 2716-2721 (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Wu, L., Iwai, M., Nakagami, H., Chen, R., Suzuki, J., Akishita, M., de Gasparo, M., Horiuchi, M.: "Effect of AT1 receptor blockade on cardiac remodeling in AT2 receptor mull mice"Arteriosclero Thromb Vasc Biol. 22. 49-54 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Suzuki, J., Iwai, M., Nakagami, H., Wu, L., Chen, R., Sugaya, T., Hamada, M., Hiwada, K., Horiuchi, M.: "Role of angiotensin II-regulated apoptosis via distinct AT1 and AT2 receptors in neointimal formation"Circulation. 106. 847-853 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Horiuchi, M., Hayashida, W., Akishita, M., Yamada, S., Lehtonen, J.Y.A., Tamura, K., Daviet, L., Y.E.Chen, Hamai, M., Cui, T-X., Iwai, M. and Minokoshi, Y.: "Interferon-g induced AT2 receptor expression in fibroblasts by Jak/STAT pathway and interferon regulatory factor-1"Circ Res. 86. 233-240 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Akishita, M., Horiuchi, M., Yamada, H., Zhang, L, Shirakami, G., Tamura, K., Ouchi, Y. and Dzau, V.J.: "Inflammation influences vascular remodering through AT2 receptor expression and signaling"Physiol Genomics. 2. 13-30 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Akishita, M., Iwai, M., Lan, W., Zhang, L., Ouchi, Y., Dzau, V.J. and Horiuchi, M.: "Inhibitory effect of AT2 receptor on coronary arterial remodeling after aortic"Circulation. 102. 1684-1689 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Wu, L., Iwai, M., Nakagami, H., Li, M., Chen, R., Suzuki, J., Akishita, M., de Gasparo, M., Horiuchi, M.: "Roles of AT2 receptor stimulation associated with selective AT1 receptor blockade with valsartan in the improvement of inflammation-induced vascular injury"Circulation. 104. 2716-2721 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Wu, L., Iwai, M., Nakagami, H., Chen, R., Suzuki, J., Akishita, M., de Gasparo, M., Horiuchi, M.: "Effect of AT1 receptor blockade on cardiac remodeling in AT2 receptor mull mice"Arteriosclero Thromb Vasc Biol. 22. 49-54 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Suzuki, J., Iwai, M., Nakagami, H., Wu, L., Chen, R., Sugaya, T., Hamada, M., Hiwada, K., Horiuchi, M.: "Role of angiotensin II-regulated apoptosis via distinct AT1 and AT2 receptors in neointimal formation"Circulation. 106. 847-853 (2002)
  • Description: 「研究成果報告書概要(欧文)」より