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Involvement of Nitric Oxide in the Inhibition of Aortic Smooth Muscle Cell Proliferation by Calcium Dobesilate
Parés-Herbuté1, Fliche, Monnier
1Laboratoire de Nutrition Humaine, Institut Universitaire de Recherche Clinique, Montpellier, France
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 both ex vivo and in 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.
Insights
Calcium dobesilate inhibits vascular smooth muscle cell proliferation, a key factor in atherosclerosis. This effect is partly mediated by nitric oxide (NO) production and protects against oxidized low-density lipoprotein (LDL) damage.
Area of Science:
- Cardiovascular Biology
- Pharmacology
- Cellular Biology
Background:
- Vascular smooth muscle cell (SMC) proliferation contributes to atherosclerosis.
- Nitric oxide (NO) inhibits SMC proliferation, while oxidized low-density lipoproteins (LDL) promote it.
- Calcium dobesilate is an angioprotective agent with potential NO-modulating and antioxidant mechanisms.
Purpose of the Study:
- To investigate the effect of calcium dobesilate on rat aortic SMC proliferation.
- To elucidate the role of nitric oxide (NO) in calcium dobesilate's mechanism of action.
- To assess calcium dobesilate's impact on LDL oxidation.
Main Methods:
- Primary rat aortic SMC cultures were used to evaluate proliferation via cell number and DNA synthesis.
- Ex vivo and in vitro treatments with varying doses and durations of calcium dobesilate were performed.
- Nitric oxide (NO) production, NO synthase activity, and LDL oxidation were measured.
Main Results:
- Calcium dobesilate administration (oral and in vitro) dose-dependently inhibited SMC proliferation and DNA synthesis.
- The inhibitory effects were reversible upon drug removal.
- Calcium dobesilate stimulated NO production and NO synthase activity, and protected against LDL oxidation.
Conclusions:
- Calcium dobesilate inhibits vascular SMC proliferation through a mechanism partly dependent on NO.
- The drug also exhibits antioxidant properties, protecting against LDL oxidation.
- Calcium dobesilate shows potential for treating vascular diseases linked to SMC proliferation.