Effect of Zinc on Vascular Smooth Muscle Cell Death Mediated by PDTC

  • Moon Sung-Kwon (Univ. of Texas Medical Branch, Div. of Cardiology and Sealy, Center for Molecular Cardiology) ;
  • Ha Sang-Do (Dept. of Industry and Technology, Korea Health Industry Development Institute)
  • Published : 2000.01.01

Abstract

Pyrrolidinedithiocarbamate (PDTC) and N-Acetylcysteine (NAC) are metal and nonmetal-chelating antioxidant which can induce rat and human smooth muscle cell death. When the smooth muscle cells from mouse aorta (MASMC) that we successfully cultured recently was exposed to PDTC and NAC in a normal serum state, the cells were induced to death by these compounds. However, PDTC did not induce the cell death in a serum depleted medium. This data suggests that certain factors in the serum may mediate the cytotoxic effect of PDTC. The metal chelator, Ca-EDTA blocked PDTC-induced cell death, but Cu-, Fe-, and Zn-EDTA did not block the PDTC-induced cell death. This data indicated that copper, iron, and zinc in the serum may lead to the cytotoxic effect of PDTC. Investigation of the intracellular zinc level in PDTC-induced smooth muscle cell death using the zinc probe dye N-(6-methoxy-8-quinolyl)-p-toluenesulfonamide shows that only the muscle-containing layers of the arteries have higher level of zinc. As expected, PDTC increased the intracellular fluorescence level of the zinc. In agreement with these results, the addition of an exogenous metal, zinc, induced the vascular aortic smooth muscle cell death which led to an increased intracellular zinc level. We concluded that PDTC induced mouse aortic smooth muscle cell death required not only zinc level but also intracellular copper and iron level. The mechanism of this antioxidant to induce vascular smooth muscle cell death may provide a new strategy to prevent their proliferation in arteriosclerotic lesions.

Keywords

References

  1. Cell v.75 Bcl-2 function in antioxidant pathway to prevent apoptosis. Hockenbery, D. M.;Z. N. Oltvai;X. M. Yin;C. L. Milliman;S. J. Korsmeyer
  2. Pharmacology v.46 N-acetylcysteine: potential for AIDS therapy. Roederer, M.;F. J. Staal;S. W. Ela;L. A. Herzenberg;L. A. Herzenberg
  3. J. Leukocyte Biol. v.55 Inhibition of activation-induced death in T cell hybridomas by thiol antioxidants: oxidative stress as a mediator of apoptosis. Sandstrom, P. A.;M. D. Mannie;T. M. Buttke
  4. Science v.262 Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Kane, D. J.;T. A. Sarafian;R. Anton;H. Hahn;E. B. Gralla;J. S. Valentine;T. Ord;D. E. Bredesen
  5. Proc. Natl. Acad. Sci. v.91 Chronic inhibition of superoxide dismutase produces apoptotic death of spinal neurons. Rothstein, J. D.;L. A. Bristol;B. Hosler;R. H. Jr. Brown;R. W. Kuncl
  6. Arch. Surg. v.129 Antioxidants modulate induction of programmed endothelial cell death (apoptosis) by endotoxin Abello, P. A.;S. A. Fidler;G. B. Bulkley;T. G. Buchman.
  7. J. Biol. Chem. v.270 Dithiocarbamates induce apoptosis in thymocytes by raising the intracellular level of redoxactive copper Nobel, C. S. I.;M. Kimland;B. Lind;S. Orrenius;A. F. G. Slater
  8. Arch. Biochem. Biophys. v.353 Dithiocarbamate toxicity toward thymocytes involves their copper-catalyzed conversion to thiuram disulfides which oxidize glutathione in a redox cycle with-out the release of reactive oxygen species Burkitt, M. J.;H. S. Bishop;L. Milne;S. Y. Tsang;G. J. Provan;C. S. I. Nobel;S. Orrenius;A. F. G. Slater
  9. Neuroscience. v.89 Zinc-induced cortical neuronal death with features of apoptosis and necrosis: mediation by free radicals. Kim, Y. H.;E. Y. Kim;B. J. Gwag;S. Sohn;J. Y. Koh
  10. J. Neurochem. v.72 Pyrrolidine dithiocarbamate induces bovine cerebral endothelial cell death by increasing the intracellular zinc level Kim, C. H.;J. H. Kim;J. Xu;C. Y. Hsu;Y. S. Ahn
  11. Nature v.362 The pathogenesis of atherosclerosis: a perspective for the 1990s. Ross, R.
  12. Circ. Res. v.70 Active oxygen species stimulate vascular smooth muscle cell growth and protooncogene expression Rao, G. N.;B. C. Berk
  13. J. Biol. Chem. v.271 Induction of apoptosis by pyrrolidinedithiocarbamate and n-acetylcysteine in vascular smooth muscle cells Tsai, J. H.;M. Jain;D. M. Hsieh;W. S. Lee;M. Yoshizumi;C. Patterson;M. A. Perrella;C. Cooke;H. Wang;E. Haber;R. Schlegel;M. E. Lee
  14. Methods Find. Exp. Clin. Pharmacol. v.8 no.6 Elemental and trace element distribution in medical samples: analysis by proton-induced X-ray emission Spieker, C., D. Heck, W. Zidek, T. Stratmann, D. P. von Bassewitz, H. Losse, H. Vetter, and H. Zumkley
  15. J. Cell Biol. v.92 Functional angiotensin II receptors in cultured vascular smooth muscle cells. Gunter, S., R. W. Alexander, W. J. Atkinson, and M. A. Jr. Gimbrone
  16. J. Immunol. Methods v.157 Use of an aqueous soluble tetrazolium/formazan assay to measure viability and proliferation of lymphokinedependent cell lines. Buttke, T. M.;J. A. McCubrey;T. C. Owen
  17. Brain Res. v.480 Translocation of zinc may contribute to seizureinduced death of neurons Frederickson, C. J.;M. D. Hernandez;J. F. McGinty