Inhibitory effect of candesartan and rosuvastatin on CD40 and MMPs expression in apo-E knockout mice - Novel insights into the role of RAS and dyslipidemid in atherogenesis

Background: There is increasing evidence of cross-talk between renin-angiotensin system (RAS) and dyslipidemia in atherogenesis mediated via activation of inflammatory cascade, involving CD40 and matrix metalloproteinases (MMPs). We postulated that inhibition of RAS with candesartan and dyslipidemia with rosuvastatin would have additive inhibitory effect on CD40 and MMPs expression and atherogenesis. Methods and Results: Apo-E knockout mice were fed high-cholesterol diet alone, or with candesartan or rosuvastatin or both. C57BL/6J mice on regular mice chow served as control. Twelve weeks later, apo-E knockout mice with high-cholesterol diet had extensive atherosclerosis, whereas C57BL/6J mice had no atherosclerosis. Candesartan and rosuvastatin alone decreased the extent of atherosclerosis. However, the combined feeding of candesartan and rosuvastatin reduced atherosclerosis in an additive fashion. The expression of CD40 and MMPs was found to be up-regulated in apo-E knockout mice. While candesartan and rosuvastatin each had a small inhibitory effect on the expression of CD40 and MMPs, the combination completely blocked the up-regulation of these inflammatory mediators. Conclusion: This study, for the first time, demonstrates that the combination of candesartan and rosuvastatin markedly affects the expression of CD40 and MMPs, resulting in a greater antiatherosclerotic effect.