Skip to main content
Log in

Exposure to oxidized low-density lipoprotein reduces activable ras protein in vascular endothelial cells

  • Articles
  • Cell and Tissue Models
  • Published:
In Vitro Cellular & Developmental Biology - Animal Aims and scope Submit manuscript

Summary

Oxidized low-density lipoprotein (ox-LDL) has been shown to alter the migratory and proliferative activities of the vascular endothelial cells (EC) in response to serum and growth factors. The mechanism underlying the antiproliferative effect of ox-LDL on vascular EC has not been fully elucidated. In this report, we show that exposure of vascular EC to ox-LDL results in a marked reduction of the membrane-associated Ras protein. Further study shows that in ox-LDL-treated EC, reduction of the membrane-associated Ras protein is correlated with a reduced amount of active Ras (Ras-guanosine triphosphate), indicating that the Ras signaling pathway is attenuated. The attenuation of the Ras signaling pathway in ox-LDL-treated EC may thus be responsible for the retarded response to the mitogenic stimulation of serum and growth factors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Armstrong, D. A. Oxidized LDL ceroid, and prostaglandin metabolism in human atherosclerosis. Med. Hypotheses 38:244–248; 1992.

    Article  PubMed  CAS  Google Scholar 

  • Björkerud, B.; Björkerud, S. Contrary effects of lightly and strongly oxidized LDL with potent promotion of growth versus apoptosis on arterial smooth muscles, macrophages, and fibroblasts. Arterioscler. Thromb. Vasc. Biol. 16:416–424; 1996.

    PubMed  Google Scholar 

  • Boulanger, C. M.; Tanner, F. C.; Bea, M. L.; Hahn, A. W.; Werner, A.; Luscher, T. F. Oxidized low density lipoproteins induce mRNA expression and release of endothelium from human and porcine endothelium. Circ. Res. 70:1191–1197; 1992.

    PubMed  CAS  Google Scholar 

  • Carlos, T. M.; Harlan, J. M. Membrane proteins involved in phagocyte adherence to endothelium. Immunol. Rev. 114:5–28; 1990.

    Article  PubMed  CAS  Google Scholar 

  • Chatterjee, S. Role of oxidized human plasma low density lipoproteins in atherosclerosis: effects on smooth muscle cell proliferation. Mol. Cell. Biochem. 111:143–147; 1992.

    Article  PubMed  CAS  Google Scholar 

  • Chatterjee, S.; Bhunia, A.; Snowden, A.; Han, H. Oxidized low density lipoproteins stimulate galatosyltransferase activity, ras activation, p44 mitogen activated protein kinase and c-fos expression in aortic smooth muscle cells. Glycobiology 7:703–710; 1997.

    Article  PubMed  CAS  Google Scholar 

  • Chen, J. K.; Hoshi, H.; McClure, D. B.; Mckeehan, W. L. Role of lipoproteins in growth of human adult arterial endothelial and smooth muscle cells in low lipoprotein-deficient serum. J. Cell. Physiol. 129:207–214; 1986.

    Article  PubMed  CAS  Google Scholar 

  • Chen, C. H.; Jiang, W.; Via, D. P.; Luo, S.; Li, T. R.; Lee, Y. T.; Henry, P. D. Oxidized low-density lipoproteins inhibit endothelial cell proliferation by suppressing basic fibroblast growth factor expression. Circulation 101:171–177; 2000.

    PubMed  CAS  Google Scholar 

  • Chin, J. H.; Azhar, S.; Hoffman, B. B. Inactivation of endothelial derived relaxing factor by oxidized lipoproteins. J. Clin. Invest. 89:10–18; 1992.

    PubMed  CAS  Google Scholar 

  • Chomczynski, P.; Sacchi, N. Single step method for RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162:156–159; 1987.

    Article  PubMed  CAS  Google Scholar 

  • Chow, S. E.; Lee, R. S.; Sih, S. H.; Chen, J. K. Oxidized LDL promotes vascular endothelial cell pinocytosis via a prooxidation mechanism. FASEB J. 12:823–830; 1998.

    PubMed  CAS  Google Scholar 

  • Cissel, D. S.; Beaven, M. A. Disruption of Raf-1/heat shock protein 90 complex and Raf signaling by dexamethasone in mast cells. J. Biol. Chem. 275:7066–7070; 2000.

    Article  PubMed  CAS  Google Scholar 

  • Cushing, S. D.; Berliner, J. A.; Valente, A. J., et al. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc. Natl. Acad. Sci. USA 87:5134–5138; 1990.

    Article  PubMed  CAS  Google Scholar 

  • Cuthbert, J. A.; Lipsky, P. E. Suppression of the proliferation of ras-transformed cells by fluoromevalonate, an inhibitor of mevalonate metabolism. Cancer Res. 55:1732–1740; 1995.

    PubMed  CAS  Google Scholar 

  • Hamsten, A.; de Faire, U.; Walldius, G.; Dahlen, G.; Szamosi, A.; Landau, C.; Blomback, M.; Wiman, B. Plasminogen activator inhibitor in plasma: risk factor recurrent myocardial infraction. Lancet 2:3–9; 1987.

    Article  PubMed  CAS  Google Scholar 

  • Havel, R. J.; Eder, H. A.; Bradgon, J. H. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J. Clin. Invest. 34:1345–1353; 1955.

    PubMed  CAS  Google Scholar 

  • Heermeier, K.; Leicht, W.; Palmetshofer, A.; Ullirich, M.; Wanner, C.; Galle, J. Oxidized LDL suppresses NF-kappa B and overcomes protection from apoptosis in activated endothelial cells. J. Am. Soc. Nephrol. 12:456–463; 2001.

    PubMed  CAS  Google Scholar 

  • Henriksen, T.; Evensen, S. A.; Caelander, B. Injury to human endothelial cells in culture induced by low density lipoproteins. Scan. J. Clin. Lab Invest. 39:361–368; 1979.

    CAS  Google Scholar 

  • Hessler, J. R.; Morel, D. W.; Lewis, L. J.; Chisolm, G. M. Lipoprotein oxidation and lipoprotein-induced cytotoxicity. Arteriosclerosis 3:215–222; 1983.

    PubMed  CAS  Google Scholar 

  • Hessler, J. R.; Robertson, A. L., Jr.; Chinsolm, G. M. LDL-induced cytotoxicity and its inhibition by HDL in human vascular smooth muscle and endothelial cells in culture. Atherosclerosis 32:213–229; 1979.

    Article  PubMed  CAS  Google Scholar 

  • Huang, J.; Mohammadi, M.; Rodrigues, G. A.; Schlessinger, J. Reduced activation of RAF-1 and MAP kinase by a fibroblast growth factor receptor mutant deficient in stimulation of phosphatidylinositol hydrolysis. J. Biol. Chem. 270:5065–5072; 1995.

    Article  PubMed  CAS  Google Scholar 

  • Kato, K.; Cox, A. D.; Hisaka, M. M.; Graham, S. M.; Buss, J. E.; Der, C. J. Isoprenoid addition to Ras protein is the critical modification for its membrane association and transformating activity. Proc. Natl. Acad. Sci. USA 89:6403–6407; 1992.

    Article  PubMed  CAS  Google Scholar 

  • Khan, B. V.; Parthasarathy, S. S.; Alexander, R. W.; Medford, R. M. Modified low density lipoprotein and its constituents augment cytokine-activated vascular cell adhesion molecule-1 gene expression in human vascular endothelial cells. J. Clin. Invest. 95:1262–1270; 1995.

    PubMed  CAS  Google Scholar 

  • Kikuchi, A.; Williams, L. T. The post-translation modification of ras p21 is important for Raf-1 activation. J. Biol. Chem. 269:20054–20059; 1994.

    PubMed  CAS  Google Scholar 

  • Liao, J. K.; Clark, S. L. Regulation of G-protein αi2 subunit expression by oxidized low-density lipoprotein. J. Clin. Invest. 95:1457–1463; 1995.

    Article  PubMed  CAS  Google Scholar 

  • Lin, S. J.; Jan, K. M.; Weinbaum, S.; Chien, S. Transendothelial transport of low density lipoprotein in association with cell mitosis in rat aorta. Arteriosclerosis 9:230–236; 1989.

    PubMed  CAS  Google Scholar 

  • Linder, V.; Lappi, D. A.; Baird, A.; Majack, R. A.; Reidy, M. A. Role of basic fibroblast growth factor in vascular lesion formation. Circ. Res. 68:106–113; 1991.

    Google Scholar 

  • Lowry, O. H.; Rosenbrough, N. J.; Farr, A. L.; Randall, R. J. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193:265–270; 1951.

    PubMed  CAS  Google Scholar 

  • Morel, D. W.; Hessler, J. R.; Chisolm, G. W. Low density lipoprotein cytotoxicity induced by free radical peroxidation of lipid. J. Lipid Res. 24:1070–1076; 1983.

    PubMed  CAS  Google Scholar 

  • Murugesan, G.; Chisolm, G. M.; Fox, P. L. Oxidized low density lipoprotein inhibits the migration of aortic endothelial cells in vitro. J. Cell Biol. 120:1011–1019; 1993.

    Article  PubMed  CAS  Google Scholar 

  • Napoli, C.; Quehenberger, O.; de Nigris, F.; Abete, P.; Glass, C. K.; Palinski, W. Midly oxidized LDL activates multiple apoptosic signaling pathways in human coronary cells. FASEB J. 14:1996–2007; 2000.

    Article  PubMed  CAS  Google Scholar 

  • Nishida, Y.; Oda, H.; Yorioka, N. Effect of lipoproteins on mesangial cell proliferation. Kidney Int. Suppl. 71:S51-S53; 1999.

    Article  PubMed  CAS  Google Scholar 

  • Ohkawa, H.; Ohishi, N.; Yagi, K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem. 95:351–358; 1979.

    Article  PubMed  CAS  Google Scholar 

  • Pomerantz, K. B.; Lander, H. M.; Summers, B.; Robishaw, J. D.; Balcueva, E.; Hajjar, D. P. G-protein-mediated signalling in cholesterol-enriched arterial smooth muscle cells. 1. Reduced membrane-associated G-protein content due to diminished isoprenylation of G-γ subunits and p21 ras. Biochemistry 36:9523–9531; 1997.

    Article  PubMed  CAS  Google Scholar 

  • Rajavashisth, T. B.; Andalibi, A.; Territo, M. C.; Berliner, J. A.; Nava, M.; Fogelman, A. M.; Lusis, A. J. Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins. Nature 344:254–257; 1990.

    Article  PubMed  CAS  Google Scholar 

  • Rangaswamy, S.; Penn, M. S.; Saidel, G. M.; Chisolm, G. M. Exogenous oxidized low density lipoprotein injures and alters the barrier function of endothelium in rats in vivo. Circ. Res. 80:37–44; 1997.

    PubMed  CAS  Google Scholar 

  • Reid, V. C.; Mitchinson, M. J.; Skepper, J. N. Cytoxicity of oxidized low-density lipoprotein to mouse peritoneal macrophages: an ultrastructural study. J. Pathol. 171:321–328; 1993.

    Article  PubMed  CAS  Google Scholar 

  • Rosenfeld, M. E.; Ross, R. Macrophage and smooth muscle cell proliferation in atherosclerotic lesions of WHHL and comparably hypercholesterolemic fat-fed rabbits. Arteriosclerosis 10:680–687; 1990.

    PubMed  CAS  Google Scholar 

  • Ross, R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362:801–809; 1990.

    Article  Google Scholar 

  • Sambrook, J.; Fritsch, E. F.; Maniatis, T. Molecular cloning: a laboratory manual. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory; 1989.

    Google Scholar 

  • Schuh, J.; Novogrodsky, A.; Haschemeyer, R. H. Inhibition of lymophocyte mitogenesis by autoxidized low-density lipoprotein. Biochem. Biophys. Res. Commun. 84:763–768; 1978.

    Article  PubMed  CAS  Google Scholar 

  • Steinberg, D. Oxidative modification of LDL and atherogenesis. Circulation 95:1062–1071; 1997.

    PubMed  CAS  Google Scholar 

  • Sugawa, M.; Ikeda, S.; Kushima, Y.; Takashima, Y.; Cynshi, O. Oxidized low density lipoprotein caused CNS neuron cell death. Brain Res. 761:165–172; 1997.

    Article  PubMed  CAS  Google Scholar 

  • Wang, D. W.; Yang, V.; Chen, J. K. Oxidized LDL inhibits vascular endothelial cell morphogenesis in culture In Vitro Cell. Dev. Biol. 33:248–255; 1997.

    CAS  Google Scholar 

  • Wheeler, D. C.; Chana, R. S.; Topley, N.; Petersen, M. M.; Davies, M.; Williams, J. D. Oxidation of low density lipoprotein by mesangial cells may promote glomerular injury. Kidney Int. 45:1628–1636; 1994.

    PubMed  CAS  Google Scholar 

  • Yang, C. M.; Chien, C. S.; Hsiaooo, L. D.; Pan, S. L.; Wang, C. C.; Chiu, C. T.; Lin, C. C. Mitogenic effect of oxidized low-density lipoprotein on vascular smooth muscle cells mediated by activation of Ras/Raf/MEK/MAPK pathway. Br. J. Pharm. 132:1531–1541; 2001.

    Article  CAS  Google Scholar 

  • Yui, S.; Sasaki, T.; Miyazaki, A.; Horiuchi, S.; Yamazaki, M. Induction of murine macrophage growth by modified LDLs. Arterioscler. Thromb. 13:331–337; 1993.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jan-Kan Chen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chow, SE., Chu, WK., Shih, S.H. et al. Exposure to oxidized low-density lipoprotein reduces activable ras protein in vascular endothelial cells. In Vitro Cell.Dev.Biol.-Animal 38, 320–325 (2002). https://doi.org/10.1290/1071-2690(2002)038<0320:ETOLDL>2.0.CO;2

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1290/1071-2690(2002)038<0320:ETOLDL>2.0.CO;2

Key words

Navigation