Combined effects of HMG-CoA-reductase inhibition and renin–angiotensin system blockade on experimental atherosclerosis

Abstract 

Therapeutic strategies to prevent atherosclerotic plaque progression and achieve plaque stabilization involve 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)-reductase inhibitors (statins) and renin–angiotensin system (RAS)-blockade, but studies investigating the potentially additive effects of a combined treatment strategy are rare. We hypothesised that the adjunction of atorvastatin with telmisartan or ramipril might achieve additional effects on experimental atherosclerosis though statin-induced lipid-lowering is lacking.

ApoE^−/− mice were fed a high-fat diet for 12 weeks and randomized to either placebo (CON), atorvastatin (ATO), ramipril (RAM), telmisartan (TEL) or RAM+ATO and TEL+ATO (N=23 per group). RAS-blockade, but not ATO, reduced systolic blood pressure. None of the treatment regimens lowered systemic cholesterol levels or lipoprotein fractions. RAM, TEL and the combined therapy, but not ATO, significantly reduced aortic lipid deposition. All substances significantly reduced monocyte chemoattracting protein (MCP)-1 concentrations, macrophages and matrixmetalloproteinase (MMP)-9 content and enhanced plaque's content of tissue inhibitor of MMP (TIMP)-1, collagen and fibrous cap thickness, resulting in an overall decrease of advanced plaques (classified as types IV–VI). Additive effects of the adjunction were observed on MMP-9 gelatinolytic activity, interleukin (IL)-6 and IL-10 plasma levels.

These results indicate that a combined treatment with RAS-blockade and statins may have additive effects on systemic cardiovascular risk markers even in the absence of lipid-reduction, although additional effects on atherosclerotic plaque progression and stability were not observed in this model.

Keywords: Atherosclerosis, Plaque stability, HMG-CoA-reductase inhibition, Renin–angiotensin system blockade, ApoE^−/− mouse