Summary
d-α-Tocopherol decreases proliferation of vascular smooth muscle cells at physiological concentrations. Cell type specificity and mitogen specificity (maximal inhibition with PDGF-BB or LDL, minimal with lysophosphatidic acid) are observed. A d-α-tocopherol inhibition target has been found at the level of protein kinase C. The inhibition is not due to a direct interaction d-α-tocopherol/ protein kinase C but presumably to a block of protein kinase C activation by post-translational modifications. PMA-induced AP-1 activation is also inhibited by d-α-tocopherol. A second d-α-tocopherol target has been found between protein kinase C and AP-1, the latter becoming activated by d-α-tocopherol in non stimulated cells as well as under conditions of protein kinase C inhibition or down regulation. The d-α-tocopherol analogue d-ß-tocopherol, provided with similar antioxidant properties, is not inhibitory for protein kinase C, AP-1 activation or proliferation. It is concluded that d-α-tocopherol acts at a cellular level by controlling the signal transduction pathway by a non-antioxidant mechanism.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
Similar content being viewed by others
References
Azzi, A., Boscoboinik, D. and Hensey, C. (1992) The protein kinase C family. Eur. J. Biochem. 208: 547–557.
Badimon, J.J., Fuster, V., Chesebro, J.H. and Badimon, L. (1993) Coronary atherosclerosis. A multifactorial disease. Circulation 87: 113–116.
Bjorkhem, I., Henriksson Freyschuss, A., Breuer, O., Diczfalusy, U., Berglund, L. and Henriksson, P. (1991) The antioxidant butylated hydroxytoluene protects against atherosclerosis. Arterioscler. Thromb. 11: 15–22.
Bondjers, G., Glukhova, M., Hansson, G.K., Postnov, Y.V., Reidy, M.A. and Schwartz, S.M. (1991) Hypertension and atherosclerosis. Cause and effect, or two effects with one unknown cause? Circulation 84: V12 - V16.
Boscoboinik, D., Szewczyk, A. and Azzi, A. (1991) Alpha-tocopherol (vitamin E) regulates vascular smooth muscle cell proliferation and protein kinase C activity. Arch. Biochem. Biophys. 286: 264–269.
Boscoboinik, D., Szewczyk, A., Hensey, C. and Azzi, A. (1991) Inhibition of cell proliferation by alphatocopherol. Role of protein kinase C. J. Biol. Chem. 266: 6188–6194.
Burton, G.W. and Ingold, K.U. (1989) Vitamin E as an in vitro and in vivo antioxidant. Ann. N. Y Acad. Sci. 570: 7–22.
Burton, G.W. and Traber, M.G. (1990) Vitamin E: antioxidant activity, biokinetics, and bioavailability. Ann. Rev. Nutr. 10: 357–382.
Chatelain, E., Boscoboinik, D.O., Bartoli, G.M., Kagan, V.E., Gey, F.K., Packer, L. and Azzi, A. (1993) Inhibition of smooth muscle cell proliferation and protein kinase C activity by tocopherols and tocotrienols. Biochim. Biophys. Acta 1176: 83–89.
Clarke, P.R., Siddhanti, S.R., Cohen, P. and Blackshear, P.J. (1993) Okadaic acid-sensitive protein phosphatases dephosphorylate MARKS, a major protein kinase C substrate. FEBS Lett. 336: 37–42.
Clowes, A.W. and Schwartz, S.M. (1985) Significance of quiescent smooth muscle migration in the injured rat carotid artery. Circ. Res. 56: 139–145.
Cushing, S.D., Berliner, J.A., Valente, A.J., Territo, M.C., Navab, M., Parhami, F., Gerrity, R., Schwartz, C.J. and Fogelman, A.M. (1990) 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.
Fuster, V., Badimon, L., Badimon, J.J. and Chesebro, J.H. (1992a) The pathogenesis of coronary artery disease and the acute coronary syndromes. N. Engl. J. Med. 326: 242–250.
Fuster, V., Badimon, L., Badimon, J.J. and Chesebro, J.H. (19926) The pathogenesis of coronary artery disease and the acute coronary syndromes. N. Engl. J. Med. 326: 310–318.
Gavino, V.C., Miller, J.S., Ikharebha, S.O., Milo, G.E. and Cornwell, D.G. (1981) Effect of polyunsaturated fatty acids and antioxidants on lipid peroxidation in tissue cultures. J. Lipid Res. 22: 763–769.
Gey, K.F. (1990) The antioxidant hypothesis of cardiovascular disease: epidemiology and mechanisms. Biochem. Soc. Trans. 18: 1041–1045.
Jialal, I. and Fuller, C.J. (1993) Oxidized LDL and antioxidants. Clin. Cardiol. 16: 16–19.
Kita, T., Nagano, Y., Yokode, M., Ishii, K., Kume, N., Ooshima, A., Yoshida, H. and Kawai, C. (1987) Probucol prevents the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbit, an animal model for familial hypercholesterolemia. Proc. Natl. Acad. Sci. USA 84: 5928–5931.
Kraft, A.S. and Anderson, W.B. (1983) Phorbol esters increase the amount of Ca2+, phospholipid-dependent protein kinase associated with plasma membrane. Nature 301: 621–623.
Kraft, A.S., Anderson, W.B., Cooper, H.L. and Sando, J.J. (1982) Decrease in cytosolic calcium/phospholipiddependent protein kinase activity following phorbol ester treatment of EL4 thymoma cells. J. Biol. Chem. 257: 13193–13196.
Kuzuya, M., Naito, M., Funaki, C., Hayashi, T., Yamada, K., Asai, K. and Kuzuya, F. (1991) Antioxidants stimulate endothelial cell proliferation in culture. Artery 18: 115–124.
Lindsey, J.A., Zhang, H.F., Kaseki, H., Morisaki, N., Sato, T. and Cornwell, D.G. (1985) Fatty acid metabolism and cell proliferation. VII. Antioxidant effects of tocopherols and their quinones. Lipids 20: 151–157.
Mochly Rosen, D., Khaner, H. and Lopez, J. (1991) Identification of intracellular receptor proteins for activated protein kinase C. Proc. Natl. Acad. Sci. USA 88: 3997–4000.
Mochly Rosen, D., Khaner, H., Lopez, J. and Smith, B.L. (1991) Intracellular receptors for activated protein kinase C. Identification of a binding site for the enzyme. J. Biol. Chem. 266: 14866–14868.
Morisaki, N., Lindsey, J.A., Stitts, J.M., Zhang, H. and Cornwell, D.G. (1984) Fatty acid metabolism and cell proliferation. V. Evaluation of pathways for the generation of lipid peroxides. Lipids 19: 381–394.
Morisaki, N., Sprecher, H., Milo, G.E. and Cornwell, D.G. (1982) Fatty acid specificity in the inhibition of cell proliferation and its relationship to lipid peroxidation and prostaglandin biosynthesis. Lipids 17: 893–899.
Morisaki, N., Yokote, K. and Saito, Y. (1992) Atherosclerosis from a viewpoint of arterial wall cell function: relation to vitamin E. J. Nutr. Sci. Vitaminol. Spec 20: 196–199.
Ozer, N.K., Palozza, P., Boscoboinik, D. and Azzi, A. (1993) d-alpha-Tocopherol inhibits low density lipoprotein induced proliferation and protein kinase C activity in vascular smooth muscle cells. FEBS Lett. 322: 307–310.
Pears, C., Stabel, S., Cazaubon, S. and Parker, P.J. (1992) Studies on the phosphorylation of protein kinase C-alpha. Biochem. J. 283: 515–518.
Pryor, A.W., Cornicelli, J.A., Devall, L.J., Tait, B., Trivedi, B.K., Witiak, D.T. and Wu, M. (1994) A rapid screening test to determine the antioxidant potencies of natural and synthetic antioxidants. J. Org. Chem. 58: 3521–3532.
Raines, E.W. and Ross, R. (1993) Smooth muscle cells and the pathogenesis of the lesions of atherosclerosis. Br. Heart J. 69: S30 - S37.
Rao, G.N. and Berk, B.C. (1992) Active oxygen species stimulate vascular smooth muscle cell growth and protooncogene expression. Circ. Res. 70: 593–599.
Rao, G.N., Lassegue, B., Griendling, K.K., Alexander, R.W. and Berk, B.C. (1993) Hydrogen peroxide-induced cfos expression is mediated by arachidonic acid release: role of protein kinase C. Nucleic. Acids. Res. 21: 1259–1263.
Rimm, E.B., Stampfer, M.J., Ascherio, A., Giovannucci, E., Colditz, G.A. and Willett, W.C. (1993) Vitamin E consumption and the risk of coronary heart disease in men. N. Engl. J. Med. 328: 1450–1456.
Ross, R. (1993) The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362: 801–809.
Ross, R. and Agius, L. (1992) The process of atherogenesis—cellular and molecular interaction: from experimental animal models to humans. Diabetologia 35 (Suppl. 2): S34 - S40.
Schwartz, C.J., Valente, A.J., Sprague, E.A., Kelley, J.L. and Nerem, R.M. (1991) The pathogenesis of atherosclerosis: an overview. Clin. Cardiol. 14: 11–16.
Schwartz, S.M., Heimark, R.L. and Majesky, M.W. (1990) Developmental mechanisms underlying pathology of arteries. Physiol. Rev. 70: 1177–1209.
Stampfer, M.J., Hennekens, C.H., Manson, J.E., Colditz, G.A., Rosner, B. and Willett, W.C. (1993) Vitamin E consumption and the risk of coronary disease in women. N. Engl. J. Med. 328: 1444–1449.
Thyberg, J., Hedin, U., Sjolund, M., Palmberg, L. and Bottger, B.A. (1990) Regulation of differentiated properties and proliferation of arterial smooth muscle cells. Arteriosclerosis 10: 966–990.
Traber, M.G., Rudel, L.L., Burton, G.W., Hughes, L., Ingold, K.U. and Kayden, H.J. (1990) Nascent VLDL from liver perfusions of cynomolgus monkeys are preferentially enriched in RRR- compared with SRR-alphatocopherol: studies using deuterated tocopherols. J. Lipid Res. 31: 687–694.
Witztum, J.L. (1993) Role of oxidised low density lipoprotein in atherogenesis. Br. Heart J. 69: S12 - S18.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1995 Birkhäuser Verlag Basel/Switzerland
About this paper
Cite this paper
Azzi, A., Boscoboinik, D., Marilley, D., Özer, N.K., Stäuble, B., Tasinato, A. (1995). Vascular smooth muscle cell proliferation is controlled by d-α-tocopherol at the level of protein kinase C and of the transcription factor AP-1. In: Cutler, R.G., Packer, L., Bertram, J., Mori, A. (eds) Oxidative Stress and Aging. Molecular and Cell Biology Updates. Birkhäuser Basel. https://doi.org/10.1007/978-3-0348-7337-6_7
Download citation
DOI: https://doi.org/10.1007/978-3-0348-7337-6_7
Publisher Name: Birkhäuser Basel
Print ISBN: 978-3-0348-7339-0
Online ISBN: 978-3-0348-7337-6
eBook Packages: Springer Book Archive