Modulatory role of chelating agents in diet-induced hypercholesterolemia in rats

Introduction: Hypercholesterolemia is a major risk factor for the development of atherosclerosis and endothelial dysfunction. Chelating agents may play a modulatory role in atherosclerosis by removal of calcium from atherosclerotic plaques. Aim: The present study aimed to explore the effects of calcium disodium ethylenediaminetetraacetic acid (CaNa2EDTA) and meso-2,3-dimercaptosuccinic acid (DMSA) on diet-induced hypercholesterolemia in rats using simvastatin as a reference standard. Methods: Hypercholesterolemia was induced by feeding rats with cholesterol-rich diet for six weeks. Rats were divided into five groups (n = 8): normal control, hypercholesterolemic control, simvastatin (20 mg/kg; p.o.), CaNa2EDTA (100 mg/kg; i.p.) and DMSA (100 mg/kg; i.p.). Treatments continued daily for the six weeks of diet feeding. Results: Diet-induced hypercholesterolemia resulted in alterations in the lipid profile markers and a state of oxidative stress coupled by compensatory increase in serum nitric oxide (NO) level and decreased aortic endothelial nitric oxide synthase (eNOS) activity parallel to increased inducible nitric oxide synthase (iNOS) activity, aortic calcium content and aortic wall thickness. Treatment with simvastatin, CaNa2EDTA and DMSA improved lipid profile and oxidative stress markers. In addition, they attenuated hypercholesterolemia-induced changes in serum NO level, aortic eNOS and iNOS activities, calcium content and aortic wall thickness. Conclusion: Pretreatment of hypercholesterolemic rats with simvastatin, CaNa2EDTA or DMSA attenuated most of the changes induced by feeding rats with cholesterol-rich diet owing to their observed anti-hyperlipidemic and antioxidant properties