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Involvement of nitric oxide in the inhibition of aortic smooth muscle cell proliferation by calcium dobesilate

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International Journal of Angiology

Abstract

Vascular smooth muscle cell (SMC) proliferation is a key process in the pathogenesis of atherosclerosis. Numerous factors are involved in the regulation of SMC growth. Nitric oxide (NO) induces the inhibition of SMC proliferation whereas oxidized low-density lipoproteins (LDL) have a mitogenic effect. Calcium dobesilate (Doxium) is an angioprotective agent for treating vascular diseases. It has been shown to increase NO production and to have antioxidant properties but its mechanism of action is not yet fully understood. This study investigated the effect of calcium dobesilate on proliferation of rat aortic SMC in culture. Proliferation was evaluated by cell number and DNA synthesis. Orally administered calcium dobesilate (30, 100, or 200 mg/kg/day for 7 days) induced a dose-dependent decrease of proliferation of SMC in primary culture compared with controls.In vitro treatment with calcium dobesilate (0.05–5 mM) inhibited both DNA synthesis and proliferation in a time- and concentration-dependent manner. In bothex vivo andin vitro models, the inhibition was reversible upon removal of the drug. Calcium dobesilate also stimulated NO production and NO synthase activity. Inhibitors of NO synthesis attenuated the inhibitory effect of calcium dobesilate (300 µM) on DNA synthesis. In addition, calcium dobesilate (2.5–40 µM) induced a dose-dependent protection of cooper-induced LDL oxidation. These results showed that calcium dobesilate inhibits SMC proliferation, partly by a NO-dependent mechanism, and suggest that it could be effective in the treatment of pathological disorders associated with vascular SMC proliferation.

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References

  1. Ross R (1993) The pathogenesis of atherosclerosis: A perspective for the 1990s. Nature (Lond) 362:801–809.

    PubMed  Google Scholar 

  2. Moncada S, Higgs A (1993) The L-arginine-nitric oxide pathway. N Engl J Med 329:2002–2012.

    PubMed  Google Scholar 

  3. Sarkar R, Webb RC (1998) Does nitric oxide regulate smooth muscle cell proliferation? J Vasc Res 35:135–142.

    PubMed  Google Scholar 

  4. Penn M, Chisolm G (1994) Oxidized lipoproteins, altered cell function and atherosclerosis. Atherosclerosis 108:S21-S29.

    PubMed  Google Scholar 

  5. Björkerud S, Björkerud B (1994) Lipoproteins are major and primary mitogens and growth promoters for human arterial smooth muscle cells and lung fibroblasts in vitro. Arterioscler Thromb 14:288–289.

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  7. Heidrich H, Gerke E, Nekarda H (1983) Inhibition of platelet aggregation under calcium dobesilate. Arzneimittelforsch/Drug Res 33:580–582.

    Google Scholar 

  8. Michal M, Giessinger N (1985) Effect of calcium dobesilate and its interaction with aspirin on thrombus formation in vivo. Thromb Res 40:215–226.

    PubMed  Google Scholar 

  9. Suschek C, Kolb H, Kolb-Bachofen V (1997) Dobesilate enhances endothelial nitric oxide synthase activity in macro- and microvascular endothelial cells. Br J Pharmacol 122:1502–1508.

    PubMed  Google Scholar 

  10. Ruiz E, Lorente R, Tejerina T (1997) Effects of calcium dobesilate on the synthesis of endothelium-dependent relaxing factors in rabbit isolated aorta. Br J Pharmacol 121:711–716.

    PubMed  Google Scholar 

  11. Brunet J, Farine JC, Garay RP, Hannaert P (1998) In vitro antioxidant properties of calcium dobesilate. Fundam Clin Pharmacol 12:205–212.

    PubMed  Google Scholar 

  12. Graber R, Farine J-C, Losa GA (1998) Calcium dobesilate protects human peripheral blood mononuclear cells from oxidation and apoptosis. Apoptosis 3:41–49.

    PubMed  Google Scholar 

  13. Parés-Herbuté N, Hillaire-Buys D, Etienne P, Gross R, Loubatières-Mariani M-M, Monnier L (1996) Adenosine inhibitory effect of enhanced growth of aortic smooth muscle cells from streptozotocine-induced diabetic rats. Br J Pharmacol 311:783–789.

    Google Scholar 

  14. Schini VB, Catovsky S, Schray-Utz B, Busse R, Vanhoutte PM (1994) Insulin-like growth factor I inhibits induction of nitric oxide synthase in vascular smooth muscle cells. Circ Res 74:24–32.

    PubMed  Google Scholar 

  15. Schumaker VN, Puppione DL (1986) Sequential flotation ultracentrifugation. Methods Enzymol 128:155–170.

    PubMed  Google Scholar 

  16. Esterbauer H, Striegl G, Puhl H, Rotheneder M (1989) Continuous monitoring of in vitro oxidation of human low density lipoprotein. Free Radic Res Comm 6:67–75.

    Google Scholar 

  17. Sinzinger H, Rauscha R, Vinazzer H (1987) Platelet function and prostaglandins in patients with peripheral vascular disease treated with calcium dobesilate. Prostaglandins Leukot Med 29:1–9.

    PubMed  Google Scholar 

  18. Benakis A, Glasson B, Bouvier CA, et al. (1974) Métabolisme et pharmacocinétique du dobésilate de calcium chez l'homme. Thérapie 29:211–219.

    Google Scholar 

  19. Inoue T, Fukuo K, Mprimoto S, Koh E, Ogihara T (1993) Nitric oxide mediates interleukin-1-induced prostaglandin E2 production by vascular smooth muscle cells. Biochem Biophys Res Commun 194:420–424.

    PubMed  Google Scholar 

  20. Garg UC, Hassid A (1989) Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 83:1774–1777.

    PubMed  Google Scholar 

  21. Chen L, Haught WH, Yang B, Saldeen TGP, Parathasarathy S, Mehta JL (1997) Preservation of endogenous antioxidant activity and inhibition of lipid peroxidation as common mechanisms of antiatherosclerotic effects of vitamin E, lovastatin and amlodipine. J Am Coll Cardiol 30:569–575.

    PubMed  Google Scholar 

  22. Guyton JR, Lenz ML, Mathews B, et al. (1995) Toxicity of oxidized low density lipoproteins for vascular smooth muscle cells and partial protection by antioxidants. Atherosclerosis 118:237–249.

    PubMed  Google Scholar 

  23. Corsini A, Mazzotti M, Raiteri M, et al. (1993) Relationship between mevalonate pathway and arterial myocyte proliferation: In vitro studies with inhibitors of HMG-CoA reductase. Atherosclerosis 101:117–125.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Laboratoire de Nutrition Humaine, Institut Universitaire de Recherche Clinique, 75, rue de la Cardonille, 34093, Montpellier Cedex 5, France

    Núria Parés-Herbute Ph.D., Elisabeth Fliche (B. Sc.Pharm.) & Louis Monnier M.D., Ph.D.

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  1. Núria Parés-Herbute Ph.D.
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  2. Elisabeth Fliche
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  3. Louis Monnier M.D., Ph.D.
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Parés-Herbute, N., Fliche, E. & Monnier, L. Involvement of nitric oxide in the inhibition of aortic smooth muscle cell proliferation by calcium dobesilate. International Journal of Angiology 8 (Suppl 1), S5–S10 (1999). https://doi.org/10.1007/BF01619842

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