Oxidized LDL receptors, LOX-1 and SE-PSOX and their soluble molecules

• Project/Area Number: 16590880
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kyoto University
• Principal Investigator: KUME Noriaki Kyoto University, Department of Cardiovascular Medicine, Associate Professor (20252455)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
• Keywords: atherosclerosis / plaque rupture / LOX-1 / acute coronary syndrome / proteases / ADAM10 / IL-18 / shedding / トロンビン / メタロプロテアーゼ / 血栓 / LOX-1 / 動脈硬化 / マクロファージ / ガンマインターフェロン / ケモカイン / 平滑筋細胞 / CXCR6

Research Abstract

Lectin-like oxidized LDL receptor-1 (LOX-1) appears to play crucial roles in atherosclerotic plaque rupture. We previously reported that circulating soluble LOX-1 (sLOX-1) levels are elevated in acute coronary syndrome (ACS) and that sLOX-1 can be a specific and sensitive biomarker for ACS. A proinflammatory cytokine interleukin 18 (IL-18) and its receptor are prominently expressed in atherosclerotic plaques. In addition, circulating IL-18 levels were reported to be high in ACS. In this study, we have examined if IL-18 can stimulate shedding of LOX-1 and subsequent release of sLOX-1. After transfection with LOX-1 cDNA, HEK-293T cells were incubated with or without IL-18. Cell-conditioned media and total cell lysates were subjected to immunoblot analyses with an anti-LOX-1 monoclonal antibody. In addition, ADAM10 cDNA, ADAM10 siRNA or control vector were also co-transfected into HEK-293T cells, and the cell-conditioned media and total cell lysates were subjected to LOX-1 immunoblotting after treatment with or without IL-18. The cell-conditioned medium/total cell lysate ratios in the amounts of LOX-1 or sLOX-1 were determined as sLOX-1 cleavage ratios. IL-18 (10-100 ng/ml) stimulation increased the sLOX-1 cleavage by 3- to 4-fold in a concentration- and time-dependent manner. ADAM10 overexpression alone similarly enhanced the sLOX-1 cleavage. ADAM10 inhibition by ADAM10 siRNA transfection significantly suppressed IL-18-induced sLOX-1 cleavage. IL-18 similarly enhanced sLOX-1 cleavage in TNF-〓-activated cultured endothelial cells, as well as LOX-1 transgenic mice in vivo. IL-18 appears one of the stimuli that enhance sLOX-1 release in ACS and ADAM10 may be involved in this process.

Research Products

• [Journal Article] CXCL16 is a novel angiogenic factor for human umbilical vein endothelial cells. (2005)
  • Author(s): Zhuge X, . Murayama T, Arai H, Yamauchi R, Tanaka M, Shimaoka T, Yonehara S, Kume N, Yokode M, Kita T
  • Journal Title: Biochem. Biophys. Res. Commun 331 Pages: 1295-1300
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Serum soluble lectin-like oxidized low-density lipoprotein receptor-1 levels are elevated in acute coronary syndrome. A novel marker for early diagnosis. (2005)
  • Author(s): Hayashida K, Kume N, Murase T, Minami M, Nakagawa D, Inada T, Tanaka M Ueda A, Kominami G, Kambara H, Kimura T, Kita T
  • Journal Title: Circulation 112 Pages: 812-818
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] CXCL16 is a novel angiogenic factor for human umbilical vein endothelial cells (2005)
  • Author(s): Xin, Zhuge, Toshinori, Murayama, Hidenori, Arai, Ryoko, Yamauchi, Makoto, Tanaka, Takeshi, Shimaoka, Shin, Yonehara, Noriaki, Kume, Masayuki, Yokode, Toru, Kita
  • Journal Title: Biochem. Biophys. Res. Commun 331 Pages: 1295-1300
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Serum soluble lectin-like oxidized low-density lipoprotein receptor-1 levels are elevated in acute coronary syndrome. A novel marker for early diagnosis (2005)
  • Author(s): Hayashida, K., Kume, N., Murase, T., Minami, M., Nakagawa, D., Inada, T., Tanaka, M., Ueda, A., Kominami, G., Kambara, H., Kimura, T., Kita, T
  • Journal Title: Circulation 112 Pages: 812-818
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] CXCL16 is a novel agiogenic factor for human umbilical vein endothelial cells. (2005)
  • Author(s): Xin Zhuge, Toshinori Murayama, Hidenori Arai, Ryoko Yamauchi, Makoto Tanaka, Takeshi Shimaoka, Shin Yonehara, Noriaki Kume, Masayuki Yokode, Toru Kita
  • Journal Title: Biochem.Biophys.Res.Commun 331 Pages: 1295-1300
• [Journal Article] Serum soluble ectin-like oxidized low-density lipoprotein recepfor-1 levels are elevated in acute coronary syndrome. A novel marker for early diagnosis. (2005)
  • Author(s): Kazutaka Hayashida, Noriaki Kume, Takatoshi Murase T, Manabu Minami, Daisuke Nakagawa, Tsukasa Inada, Masaru Tanaka Akira Ueda, Goro Kominami, Horofumi Kambara, Takeshi Kimura, Toru Kita
  • Journal Title: Circulation 112 Pages: 812-818
• [Journal Article] CXCL16 is a novel angiogenic factor for human umbilical vein endothelial cells (2005)
  • Author(s): Xin Zhuge et al.
  • Journal Title: Biochemical Biophysical Research Communication (印刷中)
• [Journal Article] Apoposis of vascular cells by oxidized LDL: involvement of caspases and LOX-1, and its implication in atherosclerotic plaque rupture. (2004)
  • Author(s): Kume N, Kita T
  • Journal Title: Circulation Research 94 Pages: 269-270
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Heparin-binding EGF-like growth factor induces expression of lectin-like oxidized-LDL receptor-1 in vascular smooth muscle cells. (2004)
  • Author(s): Mukai E, Kume N, et. al.
  • Journal Title: Atherosclerosis 176 Pages: 289-296
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Peroxisome proliferator-activated receptor alpha ligands activate transcription of lectin-like oxidized LDL rceptor-1 gene through GC box motif (2004)
  • Author(s): Hayashida K, Kume N, et. al.
  • Journal Title: Biochemical Biophysical Research Communication 323 Pages: 1116-1123
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Upregulation of SR-PSOX/CXCL16 and recruitment of CD8+T cells in cardiac Valves in inflammatory valvular heart disease. (2004)
  • Author(s): Yamauchi R, Tanaka M, Kume N, et. al.
  • Journal Title: Arteriosclerosis, Thrombosis and Vascular Biology 24 Pages: 282-287
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Chemokines generally exhibit scavenger receptor activity through their receptor-binding domain. (2004)
  • Author(s): Shimaoka T, Nakayama T, Hieshima K,
  • Journal Title: Journal of Biological Chemistry 279 Pages: 26807-26810
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Apoposis of vascular cells by oxidized LDL : involvement of cspases and LOX-1, and its implication in atherosclerotic plaque rupture (2004)
  • Author(s): Kume, N., Kita, T
  • Journal Title: Circulation Research 94 Pages: 269-270
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Heparin-binding EGF-like growth factor induces expression of lectin-like oxidized LDL receptor-1 in vascular smooth muscle cells (2004)
  • Author(s): Mukai, E., Kume, N., et. al.
  • Journal Title: Atherosclerosis 176 Pages: 289-296
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Peroxisome proliferator-activated receptor alpha ligands activate transcription of lectin-like oxidized LDL receptor-1 through GC box motif (2004)
  • Author(s): Hayashida, K., Kume, N., et. al.
  • Journal Title: Biochemical Biophysical Research Communication 323 Pages: 1116-1123
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Upregulation of SR-PSOX/CXCL16 and recruitment of CD8+T cells in cardiac valves during inflammatory valvular heart disease (2004)
  • Author(s): Yamauchi, R., Tanaka, M., Kume, N., et. al.
  • Journal Title: Arteriosclerosis, Thrombosis and Vascular Biology 24 Pages: 282-287
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Chemokines generally exhibit scavenger receptor activity through their receptor-binding domain (2004)
  • Author(s): Shimaoka, T., Nakayama, T., Hieshima, K
  • Journal Title: Journal of Biological Chemistry 279 Pages: 26807-26810
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Apoposis of vascular cells by oxidized LDL : involvement of spases and LOX-1 and (2004)
  • Author(s): Kume N, Kita T
  • Journal Title: Circulation Research 94巻 Pages: 269-270
• [Journal Article] Heparin-binding EGF-like growth factor induces expression of lectin-like oxidized (2004)
  • Author(s): Mukai E, Kume N, et al.
  • Journal Title: Ahterosclerosis 176巻 Pages: 289-296
• [Journal Article] Peroxisome proliferator-activated receptor alpha ligands activate transcription of lectin- (2004)
  • Author(s): Hayashida K, Kume N, et al.
  • Journal Title: Biochemical Biophysical Research Communication 323巻 Pages: 1116-1123
• [Journal Article] Upregulation of SR-PSOX/CXCL16 and recruitment of CD8+T cells in cardiac (2004)
  • Author(s): Yamauchi R, Tanaka M, Kume N, et al.
  • Journal Title: Arteriosclerosis, Thrombosis and Vascular Biology 24巻 Pages: 282-287
• [Journal Article] Chemokines generally exhibit scavenger receptor activity through their receptor-binding domain (2004)
  • Author(s): Shimaoka T, Nakayama T, Hieshima K
  • Journal Title: Journal of Biological Chemistry 279巻 Pages: 26807-26810