Clarification of the mechanisms of cardiovascular dysfunction and the resultant organ failure

• Project/Area Number: 18390078
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: SAWAMURA Tatsuya National Cardiovascular Center Research Institute, Department of Vascular Physiology, National Cardiovascular Center Research Institute, Director (30243033)
• Co-Investigator(Kenkyū-buntansha): MASAKI Tomoo Tokyo Women's Medical University, 付置研究所, 特任教授 (60009991)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥16,830,000 (Direct Cost: ¥14,700,000、Indirect Cost: ¥2,130,000); Fiscal Year 2007: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000); Fiscal Year 2006: ¥7,600,000 (Direct Cost: ¥7,600,000)
• Keywords: LOX-1 / oxidized LDL / endothelial cells / atherosclerosis / thrombosis / intimal hyperplasia / 酸化LDL受容体

Research Abstract

Accumulating evidence suggests significance of the oxidized LDL receptor LOX-1 in endothelial and vascular dysfunction. In this study, we generated LOX-1 KO mice to address the role of LOX-1 in atherosclerotic diseases. With the KO mice, we obtained following results. (1) LOX-1 KO mice were resistant to the suppressive effects of oxidized LDL on endothelium-dependent relaxation. (2) Atherosclerosis induced by high fat diet was delayed in LOX-1 KO mice compared with wild type mice in both C57BL/6 and LDLRKO-C57BL/6 background. (3) Myocardial infarction and cardiac remodeling induced by LASD ligation was suppressed and cardiac function was relatively preserved in LOX-1 KO mice compared with wild type. (4) Both platelet aggregation in vitro and FeC12-induced thrombosis in vivo were suppressed in LOX-1 KO mice compared with wild type. Thus, we have demonstrated that LOX-1 aggravates every phase of atherosclerotic diseases, i.e. endothelial dysfunction, atherosclerosis, thrombosis, and myocardial infarction.

Research Products

• [Journal Article] LOX-1 abrogation reduces myocardial ischemia-reperfusion injury in mice. (2008)
  • Author(s): Hu, C., Chen, J., Dandapat, A., Fujita, Y., Inoue, N., Kawase, Y., Jishage, K., Suzuki, H., Li, D., Hermonat, P.L., Sawamura, T.and Mehta, J.L.
  • Journal Title: J Mol Cell Cardiol 44 Pages: 76-83
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Electronegative LDL circulating in smokers impairs endothehal progenitor cell differentiation by inhibiting Akt phosphorylation via LOX-1. (2008)
  • Author(s): Tang, D., Lu, J., Walterscheid, J.P., Chen, H.H., Engler, D.A., Sawamura, T., Chang, P. Y., Safi, H.J., Yang, C.Y. and Chen, C.H.
  • Journal Title: J Lipid Res 49 Pages: 33-47
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Importance of forkhead transcription factor Fkh 118 for development of testicular vasculature. (2008)
  • Author(s): Sato, Y., Baba, T., Zubair, M., Miyabayashi, K., Toyama, Y., Maekawa, M., Owaki, A., Mizusaki, H., Sawamura, T., Toshimori, K., Morohashi, K.I. and Katoh-Fukui, Y.
  • Journal Title: Mol Reprod Dev (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Deletion of LOX-1 reduces atherogenesis in LDLR knockout mice fed high cholesterol diet. (2007)
  • Author(s): Mehta, J.L.
  • Journal Title: Circ Res 100 Pages: 281-290
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Modulation of ADP-induced platelet activation by aspirin and pravastatin: role of lectin-like oxidized low-density lipoprotein receptor-1, nitric oxide, oxidative stress, and inside-out integrin signaling. (2007)
  • Author(s): Marwali, M.R.,
  • Journal Title: J Pharmacol Exp Ther 322 Pages: 1634-1642
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Lectin-like oxidized LDL receptor-1 as extracellular chaperone receptor: Its versatile functions and human diseases. (2007)
  • Author(s): Inoue, N
  • Journal Title: Methods 43 Pages: 218-222
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] LOX-1 deletion alters signals of myocardial remodeling immediately after ischemia-reperfusion. (2007)
  • Author(s): Hu, C.
  • Journal Title: Cardiovasc Res 76
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] LOX-1 abrogation reduces myocardial ischemia-reperfusion injury in mice. (2007)
  • Author(s): Hu, C.
  • Journal Title: J Mol Cell Cardiol 44 Pages: 76-83
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Electronegative LDL circulating in smokers impairs endothelial progenitor cell differentiation by inhibiting Akt phosphorylation via LOX-1. (2007)
  • Author(s): Tang, D.
  • Journal Title: J Lipid Res 49 Pages: 33-47
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Determination of LOX-1-ligand activity in mouse plasma with a chicken monoclonal Antibody for ApoB. (2007)
  • Author(s): Sato, Y
  • Journal Title: Mol Reprod Dev 49 Pages: 33-47
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Possible involvement of the oxidized low-density lipoprotein/lectin-like oxidized low-density lipoprotein receptor-1 system in pathogenesis and progression of human osteoarthritis. (2007)
  • Author(s): Akagi, M., Kanata, S., Mori, S., Itabe, H., Sawamura, T. and Hamanishi, C.
  • Journal Title: Osteoarthritis Cartlage 15 Pages: 281-290
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Deletion of LOX-1 reduces atherogenesis in LDLR knockout mice fed high cholesterol diet. (2007)
  • Author(s): Mehta, J. L., Sanada, N., Hu, C.P., Chen, J., Dandapat, A., Sugawara, F., Satoh, H., Inoue, K., Kawase, Y., Jishage, K., Suzuki, H., Takeya, M., Schnackenberg, L., Beger, R., Hermonat, P. L., Thomas, M. and Sawamura, T.
  • Journal Title: Circ Res 100 Pages: 1634-1642
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Modulation of ADP-induced platelet activation by aspirin and pravastatin : role of lectin-like oxidized low-density lipoprotein receptor-1, nitric oxide, oxidative stress, and inside-out integrin signaling. (2007)
  • Author(s): Marwali, M.R., Hu, C.P., Mohandas, B., Dandapat, A., Deonikar, P., Chen, J., Cawich, I., Sawamura, T., Kavdia, M. and Mehta, J.L.
  • Journal Title: J Pharmacol Exp Ther 322 Pages: 1324-1332
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Lectin-like oxidized LDL receptor-1 as extracellular chaperone receptor : Its versatile functions and human diseases. (2007)
  • Author(s): Inoue, N. and Sawamura, T.
  • Journal Title: Methods 43 Pages: 218-222
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] LOX-1 deletion alters signals of myocardial remodeling immediately after ischemia-reperfuision. (2007)
  • Author(s): Hu, C., Dandapat, A., Chen, J., Fujita, Y., Inoue, N., Kawase, Y., Jishage, K., Suzuki, H., Sawamura, T. and Mehta, J.L.
  • Journal Title: Cardiovasc Res 76 Pages: 292-302
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Deletion of LOX-1 reduces atherogenesis in LDLR knockout mice fed high cholesterol diet. (2007)
  • Author(s): Mehta, J. L.
  • Journal Title: Circ Res 100 Pages: 281-290
  • Peer Reviewed
• [Journal Article] Modulation of ADP-induced platelet activation by aspirin and pravastatin : role of lectin-like oxidized low-density lipoprotein receptor-l, nitric oxide, oxidative stress, and inside-out integrin signaling. (2007)
  • Author(s): Marwali, M. R.
  • Journal Title: J Pharmacol Exp Ther 322 Pages: 1634-1642
  • Peer Reviewed
• [Journal Article] Lectin-like oxidized LDL receptor-l as extracellular chaperone receptor : Its versatile functions and human diseases. (2007)
  • Author(s): Inoue, N
  • Journal Title: Methods 43 Pages: 218-222
  • Peer Reviewed
• [Journal Article] Importance of forkhead transcription factor Fkhl18 for development of testicular vasculature. (2007)
  • Author(s): Sato, Y
  • Journal Title: Mol Reprod Dev 49(in press)
  • Peer Reviewed
• [Journal Article] Oxidized low density lipoprotein impairs endothelial progenitor cells by regulation of endothelial nitric oxide synthase. (2006)
  • Author(s): Ma, F.X.
  • Journal Title: J Lipid Res 47 Pages: 1227-1237
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Dominant-negative LOX-1 blocks homodimerization of wild-type LOX-1-induced cell proliferation through extracellular signal regulated kinase 1/2 activation. (2006)
  • Author(s): Tanigawa, H
  • Journal Title: Hypertension 48 Pages: 294-300
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Cyclic tensile stretch load and oxidized low density lipoprotein synergistically induce lectin-like oxidized LDL receptor-1 in cultured bovine chondrocytes, resulting in decreased cell viability and proteoglycan synthesis. (2006)
  • Author(s): Akagi, M
  • Journal Title: J Orthop Res 24 Pages: 1782-1790
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Oxidized LDL binding to LOX-1 upregulates VEGF expression in cultured bovine chondrocytes through activation of PPAR-gamma. (2006)
  • Author(s): Kanata, S
  • Journal Title: Biochem Biophys Res Commun 348 Pages: 1003-1010
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Low-density lipoprotein oxidized to various degrees activates ERK1/2 through LOX-1. (2006)
  • Author(s): Tanigawa, H
  • Journal Title: Atherosclerosis 188 Pages: 245-250
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Antioxidants Suppress Plasma Levels of Lectinlike Oxidized Low-Density Lipoprotein Receptor-Ligands and Reduce Atherosclerosis in Watanabe Heritable Hyperlipidemic Rabbits. (2006)
  • Author(s): Oka, K
  • Journal Title: J Cardiovasc Pharmacol 48 Pages: 177-183
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Possible involvement of the oxidized low-density lipoprotein/lectin-like oxidized low-density lipoprotein receptor-1 system in pathogenesis and progression of human osteoarthritis. (2006)
  • Author(s): Akagi, M.
  • Journal Title: Osteoarthritis Cartilage 15 Pages: 281-290
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Oxidized low density lipoprotein impairs endothelial progenitor cells by regulation of endothelial nitric oxide synthase. (2006)
  • Author(s): Ma, F. X., Zhou, B., Chen, Z., Ren, Q., Lu, S.H., Sawamura, T. and Han, Z. C.
  • Journal Title: J Lipid Res 47 Pages: 1227-1237
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Dominant-negative LOX-1 blocks homodimenzation of wild-type LOX-1-induced cell proliferation through extracellular signal regulated kinase 1/2 activation. (2006)
  • Author(s): Tanigawa, H., Miura, S., Matsuo, Y., Fujino, M., Sawamura, T. and Saku, K.
  • Journal Title: Hypertension 48 Pages: 294-300
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cyclic tensile stretch load and oxidized low density lipoprotein synergistically induce lectin-like oxidized LDL receptor-1 in cultured bovine chondrocytes, resulting in decreased cell viability and proteoglycan synthesis. (2006)
  • Author(s): Akagi, M., Nishimura, S., Yoshida, K., Kakinuma, T., Sawamura, T. Munakata, H. and Hamanishi, C.
  • Journal Title: J Orthop Res 24 Pages: 1782-1790
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Oxidized LDL binding to LOX-1 upregulates VEGF expression in cultured bovine chondrocytes through activation of PPAR-gamma. (2006)
  • Author(s): Kanata, S., Akagi, M., Nishimura, S., Hayakawa, S., Yoshida, K., Sawamura, T., Munakata, H. and Hamanishi, C.
  • Journal Title: Biochem Biophys Res Commun 348 Pages: 1003-1010
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Low-density lipoprotein oxidized to various degrees activates ERK1/2 through LOX-1. (2006)
  • Author(s): Tanigawa, H., Miura, S., Zhang, B., Uehara, Y., Matsuo, Y., Fujino, M., Sawamura, T. and Saku, K.
  • Journal Title: Atherosclerosis 188 Pages: 245-250
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Antioxidants Suppress Plasma Levels of Lectinlike Oxidized Low-Density Lipoprotein Receptor-Ligands and Reduce Atherosclerosis in Watanabe Heritable Hyperlipidemic Rabbits. (2006)
  • Author(s): Oka, K., Yasuhara, M., Suzumura, K., Tanaka, K. and Sawamura, T.
  • Journal Title: J Cardiovasc Pharmacol 48 Pages: 177-183
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Oxidized low density lipoprotein impairs endothelial progenitor cells by regulation of endothelial nitric oxide synthase (2006)
  • Author(s): Ma, F.X.
  • Journal Title: J Lipid Res 47 Pages: 1227-1237
• [Journal Article] Cyclic tensile stretch load and oxidized low density lipoprotein synergistically induce lectin-like oxidized LDL receptor-1in cultured bovine chondrocytes, resulting in decreased cell viability and proteoglycan synthesis. (2006)
  • Author(s): Akagi, M
  • Journal Title: J Orthop Res 24 Pages: 1782-1790
• [Journal Article] Oxidized LDL binding to LOX-1upregulates VEGF expression in cultured bovine chondrocytes through activation of PPAR-gamma. (2006)
  • Author(s): Kanata, S
  • Journal Title: Biochem Biophys Res Commun 348 Pages: 1003-1010
• [Journal Article] Low-density lipoprotein oxidized to various degrees activates ERK1/2 through LOX-1 (2006)
  • Author(s): Tanigawa, H
  • Journal Title: Atherosclerosis 188 Pages: 245-250
• [Journal Article] Possible involvement of the oxidized low-density lipoprotein/lectin-like oxidized low-density lipoprotein receptor-1 system in pathogenesis and progression of human osteoarthritis. (2006)
  • Author(s): Akagi, M
  • Journal Title: Osteoarthritis Cartilage 15 Pages: 281-290
• [Presentation] 血栓形成過程におけるLOX-1の意義 (2008)
  • Author(s): 乙井 一典
  • Organizer: 第81回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2008-03-18
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] 動脈硬化初期病変としての血管内脂肪沈着におけるLOX-1の意義 -SHRSPラットを用いた検討- (2008)
  • Author(s): 井上 信孝
  • Organizer: 第81回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2008-03-17
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] ニワトリ抗ApoB抗体によるマウス血中のLOX-1リガンド活性測定. (2008)
  • Author(s): 佐藤 優子
  • Organizer: 第81回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2008-03-17
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] 動脈硬化初期病変としての血管内脂肪沈着におけるLOX-1の意義-SHRSPラットを用いた検討- (2008)
  • Author(s): 井上 信孝
  • Organizer: 第81回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2008-03-17
• [Presentation] LOX-1 is Involved in high fat diet-induced arterial lipid-deposition in SHR-SP. (2007)
  • Author(s): 沢村 達也
  • Organizer: 13th World Congress on Heart Disease
  • Place of Presentation: The Hyatt Regency Vancouver
  • Year and Date: 2007-07-30
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] LOX-1 is Involved in high fat diet-induced arterial lipid-deposition in SHR-SP. (2007)
  • Author(s): Tatsuya Sawamura
  • Organizer: 3th World Congress on Heart Disease
  • Place of Presentation: The Hyatt Regency Vancouver
  • Year and Date: 2007-07-30
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] LOX-1 as a potential therapeutic target for cardiovascular disease. (2007)
  • Author(s): 沢村 達也
  • Organizer: XIX World Congress of the ISHR
  • Place of Presentation: Palazzo della Cultura e dei Congressi
  • Year and Date: 2007-06-23
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] LOX-1 as a potential therapeutic target for cardiovascular disease. (2007)
  • Author(s): 沢村 達也
  • Organizer: X IX World Congress of the ISHR
  • Place of Presentation: Palazzo della Cultura e dei Congressi
  • Year and Date: 2007-06-23