Elucidation of C-reactive proteins in atherosclerosis

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 16390089
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: University of Yamanashi (2006); University of Tsukuba (2004-2005)
• Principal Investigator: FAN Jianglin University of Yamanashi, Interdisciplinary Graduate School of Medicine and Engineering, Professor, 医学工学総合研究部, 教授 (60272192)
• Co-Investigator(Kenkyū-buntansha): SUGIYAMA Fumihiro University of Tsukuba, Graduate School of Comprehensive Human Sciences, Associate Professor, 大学院人間総合科学研究所, 助教授 (90226481) ; YAMADA Nobuhiro University of Tsukuba, Graduate School of Comprehensive Human Sciences, Professor, 大学院人間総合科学研究所, 教授 (40200729) ; WATANABE Teruo Saga University, Honorary Professor, 名誉教授 (40037396) ; MORIMOTO Masatoshi Saga University, Analytic Research Center of Experimental Sciences, Associate Professor, 総合分析実験センター・生物資源開発部門, 助教授 (90136482)
• Project Period (FY): 2004 – 2006
• Keywords: Transgenic rabbits / CRP / Atherosclerosis / Hypercholesterolemia / Macrophages / Plaque / Animal model / Inflammation

Research Abstract

In this project, we have performed two studies in order to elucidate the functional roles of CRP in atherosclerosis. In the initial study, we used both human and rabbit specimens in attempt to clarify (1) whether CRP is present in the lesions, (2) if so, where CRP is deposited, (3) whether vascular cells especially macrophages can synthesize CRP. Our study showed that CRP is ubiquitously present in the lesions regardless of the lesion stage. CRP is closely associated with apoB but not macrophages. Using both Northern blotting and real-time RT-PCR, we demonstrated that CRP mRNA is basically expressed in the liver but rarely, if any, by macrophages. We also demonstrated that in hypercholesterolemic rabbits, the aortic lesion size is positively correlated with the levels of plasma CRP. In order to demonstrate whether CRP is directly involved in the lesion formation, we also generate transgenic rabbits expressing human CRP in the liver. For this study, we used a liver-specific expression construct along with insulators and established three independent lines of CRP transgenic rabbits. Now, we are using these CRP transgenic rabbits to perform atherosclerosis study. We also obtained CRP inhibitors from ISIS company and hope to investigate whether inhibition of CRP can prevent atherosclerosis.

Research Products

• [Journal Article] Increased expression of VEGF in kidney leads to progressive impairment of gomerular functions in transgenic rabbits. (2007)
  • Author(s): Liu, E., Morimoto, M., Kitajima, S., Yu, Y., Koike, T., Shiiki, H., Nagata, M., Watanabe, T., Fan, J.
  • Journal Title: J Am Soc Nephrol (In press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Lp(a) enhances coronary atherosclerosis in transgenic Watanabe heritable hyperlipidemic rabbits. (2007)
  • Author(s): Kitajima, S., Jin, Y., Koike, T., Yu, Y., Liu, E., Shiomi, M., Marcovina, SM., Morimoto, M., Watanabe, T., Fan, J.
  • Journal Title: Atherosclerosis (In press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Increased expression of VEGF in kidney leads to progressive impairment of glomerular functions (2007)
  • Author(s): Liu E, Morimoto M, Kitajima S, Yu Y, Koike T, Shiiki H, Nagata M, Watanabe T, Fan J
  • Journal Title: J Am Soc Nephrol (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Lp(a) enhances coronary atherosclerosis in transgenic Watanabe heritable hyperlipidemic rabbits (2007)
  • Author(s): Kitajima S, Jin Y, Koike T, Yu Y, Liu E, Morimoto M, Shiomi M, Marcovina S, Watanabe N, Fan J
  • Journal Title: Atherosclerosis (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Source(s) of CRP in atherosclerotic lesions. (2006)
  • Author(s): Fan, J., Chen, YE.
  • Journal Title: Am J Pathol. 168 Pages: 1054-1056
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Macrophage Metalloelastase accelerates the progression of atherosclerosis in transgenic rabbits. (2006)
  • Author(s): Liang, J., Liu, E., Yu, Y., Kitajima, S., Koike, T., Jin, Y., Morimoto, M., Hatakeyama, K., Asada, Y., Watanabe, T., Sasaguri, Y., Watanabe, S., Fan, J.
  • Journal Title: Circulation 113 Pages: 1993-2001
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Source(s) of CRP in atherosclerotic lesions (2006)
  • Author(s): Fan J, Chen YE
  • Journal Title: Am J Pathol 168 Pages: 1054-1056
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Macrophage elastase (MMP-12) accelerates the progression of atherosclerosis in transgenic rabbits (2006)
  • Author(s): Liang J, Liu E, Koike T, Yu Y, Kitajima Yingji J, Morimoto M, Watanabe T, Sasaguri Y, Watanabe S, Fan J 5, Yingji J, Morimoto M, Watanabe T, Sasaguri Y, Watanabe S, Fan J
  • Journal Title: Circulation 113 Pages: 1993-2001
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] C-Reactive Procein in Atherosclerotic Lesions its Origin and Pathophysiologieal Significance. (2005)
  • Author(s): Sun, H., Koike, T., Ichikawa, T., Hatakeyama, K., Shiomi, M., Zhang, B., Kitajima, S., Morimoto, M., Watanabe, T., Asada, Y., Chen, YE., Fan, J.
  • Journal Title: Am J Pathol 167 Pages: 1139-1148
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Enhanced aortic atherosclerosis in transgenic Watanabe heritable hyperlipidemic rabbits expressing lipoprotein lipase. (2005)
  • Author(s): Koike, T., Liang, J., Wang, X., Ichikawa, T., Shiomi, M., Sun, H., Watanabe, T., Liu, G., Fan, J.
  • Journal Title: Cardiovascular Research 65 Pages: 524-534
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Macrophage-derived lipoprotein lipase increases aortic atherosclerosis in cholesterol-fed Tg rabbits. (2005)
  • Author(s): Ichikawa, T., Liang, J., Kitajima, S., Koike, T., Wang, X., Sun, H., Morimoto, M., Shikama, H., Watanabe, T., Yamada, N., Fan, J.
  • Journal Title: Atherosclerosis 179 Pages: 87-95
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] High lipoprotein lipase activity increases insulin sensitivity in transgenic rabbits. (2005)
  • Author(s): Liu, E., Kitajima, S., Higaki, Y., Morimoto, M., Sun, H., Watanabe, T., Yamada, N., Fan, J.
  • Journal Title: Metabolism Clinical and Experimental 54 Pages: 132-138
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Transgenic rabbits with increased VEGF expression develop hemangiomas in the liver : a new model for Kasabach-Merritt syndrome. (2005)
  • Author(s): Kitajima, Shuji., Liu, E., Morimoto, M., Koike, T., Yu, Y., Watanabe, T., Imagawa, S., Fan, J.
  • Journal Title: Laboratory Investigation 85 Pages: 1517-1527
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Establishment of a SPF Colony of Human Apo(a) Transgenic Rabbits by Frozen-Thawed Embryo Transfer (2005)
  • Author(s): Watanabe, N., Nakagawa, H., Kitajima, S., Liu, E., Morimoto, M., Watanabe, T., Fan, J.
  • Journal Title: Exp. Anim. 54・4 Pages: 353-357
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] C-reactive protein in atherosclerotic lesions : its origin and pathophysiological significance (2005)
  • Author(s): Sun H, Koike T, Ichikawa T, Hatakeyama K, Shiomi M, Zhang B, Kitajima S, Morimoto M, Watanabe T, Asada Y, Chen YE, Fan J
  • Journal Title: Am J Pathol 167 Pages: 1139-1148
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Transgenic rabbits with increased VEGF expression develop hemangiomas in the liver : a new model for Kasabach-Merritt syndrome (2005)
  • Author(s): Kitajima S, Liu E, Morimoto M, Koike T, Yu Y, Watanabe T, Imagawa S, Fan J
  • Journal Title: Lab Invest 85 Pages: 1517-1527
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Establishment of a SPF colony of human apo(a) transgenic rabbits by frozen-thawed embryo transfer (2005)
  • Author(s): Watanabe N, Nakagawa H, Kitajima S, Liu E, Morimoto M, Watanabe T, Fan J
  • Journal Title: Exp Anim 54 Pages: 353-357
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Macrophage-derived lipoprotein lipase increases aortic atherosclerosis in cholesterol-fed transgenic rabbits (2005)
  • Author(s): Ichikawa T, Liang J, Kitajima S, Koike T, Wang X, Sun H, Morimoto M, Shikama H, Watanabe T, Yamada N, Fan J
  • Journal Title: Atherosclerosis 179 Pages: 87-95
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] High lipoprotein lipase increases insulin sensitivity in transgenic rabbits (2005)
  • Author(s): Liu E, Kitajima S, Morimoto M, Sun H, Watanabe T, Yamada N, Fan J
  • Journal Title: Metabolism 54 Pages: 132-138
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Enhanced atherosclerosis in WHHL transgenic rabbits expressing lipoprotein lipase (2005)
  • Author(s): Koike T, Liang J, Shiomi M, Ichikawa T, Wang X, Sun H, Shikama H, Watanabe T, Liu G, Fan J
  • Journal Title: Cardiovasc Res 65 Pages: 524-534
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association of Increased Expression of Macrophage Elastase (Matrix Metalloproteinase 12) With Rheumatoid Arthritis. (2004)
  • Author(s): Liu, M., Sun, H., Wang, X., Koike, T., Mishima, H., Ikeda, K., Watanabe, T., Ochiai, N., Fan, J.
  • Journal Title: Arthritis ＆ Rheumatism 50・10 Pages: 3112-3117
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Overexpression of Human Matrix Metalloproteinase-12 Enhances the Development of Inflammatory Arthritis in Transgenic Rabbits. (2004)
  • Author(s): Wang, X., Liang, J., Koike, T., Sun, H., Ichikawa, T., Kitajima, S., Morimoto, M., Shikama, H., Watanabe, T., Sasaguri, Y., Fan, J.
  • Journal Title: Am J Pathol 165 Pages: 1375-1383
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Overexpression of lipoprotein lipase in transgenic rabbits leads to increased small dense LDL in plasma and promotes atherosclerosis. (2004)
  • Author(s): Ichikawa, T., Kitajima, S., Liang, J., Koike, T., Wang, X., Sun, H., Okazaki, M., Morimoto, M., Shikama, H., Watanabe, T., Yamada, N., Fan, J.
  • Journal Title: Laboratory Investigation 84 Pages: 715-726
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Overexpression of lipoprotein lipase improves insulin resistance induced by a high-fat diet in transgenic rabbits. (2004)
  • Author(s): Kitajima, S., Morimoto, M., Liu, E., Koike, T., Higaki, Y., Taura, Y., Mamba, K., Itamoto, K., Watanabe, T., Tsutsumi, K., Yamada, N., Fan, J.
  • Journal Title: Diabetologia 47 Pages: 1202-1209
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Overexpression of Lipoprotein Lipase in Transgenic Watanabe Heritable Hyperlipidemic Rabbits Improves Hyperlipidemia and Obesity. (2004)
  • Author(s): Koike, T., Liang, J., Wang, X., Ichikawa, T., Shiomi, M., Liu, G., Sun, H., Kitajima, S., Morimoto, M., Watanabe, T., Yamada, N., Fan, J.
  • Journal Title: J Biol Chem 279・9 Pages: 7521-7529
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Macrophage-specific overexpression of human matrix metalloproteinase-12 in transgenic rabbits. (2004)
  • Author(s): Fan, J., Wang, X., Wu, L., Matsumoto, S., Liang, J., Koike, T., Ichikawa, T., Sun, H., Shikama, H., Sasaguri, Y., Watanabe, T.
  • Journal Title: Transgenic Research 13 Pages: 261-269
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Overexpression of lipoprotein lipase improves insulin resistance induced by a high-fat diet in transgenic rabbits (2004)
  • Author(s): Kitajima S, Morimoto M, Liu E, Koike T, Higaki Y, Taura Y, Mamba K, Itamoto K Watanabe T, Tsutsumi K, Yamada N, Fan J
  • Journal Title: Diabetologia 47 Pages: 1202-1209
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Overexpression of lipoprotein lipase in transgenic Watanabe heritable hyperlipidemic rabbits improves hyperlipidemia and obesity (2004)
  • Author(s): Koike T, Liang J, Wang X, Ichikawa T, Shiomi M, Liu G, Sun H, Kitajima S, Morimoto M, Watanabe T, Yamada N, Fan J
  • Journal Title: J Biol Chem 279 Pages: 7521-7529
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Overexpression of lipoprotein lipase in transgenic rabbits leads to increased small dense LDL in plasma and promotes atherosclerosis (2004)
  • Author(s): Ichikawa T, Kitajima S, Liang J, Koike T, Wang X, Sun H, Okazaki M, Morimoto M, Shikama H, Watanabe T, Yamada N, Fan J
  • Journal Title: Lab Invest 84 Pages: 715-726
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Macrophage-specific overexpression of human matrix metalloproteinase-12 in transgenic rabbits (2004)
  • Author(s): Fan J, Wang X, Wu L, Matsumoto S, Liang J, Koike T, Ichikawa T, Sun H, Shikama H, Sasaguri Y, Watanabe T
  • Journal Title: Transgenic Res 13 Pages: 261-269
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Overexpression of human matrix metalloproteinase-12 enhances the development of inflammatory arthritis in transgenic rabbits (2004)
  • Author(s): Wang X, Liang J, Koike T, Sun H, Ichikawa T, Kitajima S, Morimoto M, Shikama H, Watanabe T, Sasaguri Y, Fan J
  • Journal Title: Am J Pathol 165 Pages: 1375-1383
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association of increased expression of macrophage elastase (MMP-12) with rheumatoid arthritis (2004)
  • Author(s): Liu M, Sun H, Wang X, Koike T, Mishima H, Ikeda K, Watanabe T, Ochiai N, Fan J
  • Journal Title: Arth Rheum 50 Pages: 3112-3117
  • Description: 「研究成果報告書概要(欧文)」より