Resveratrol protects against atherosclerosis, but does not add to the antiatherogenic effect of atorvastatin, in APOE*3-Leiden.CETP mice

Abstract

Resveratrol is a major constituent of traditional Asian medicinal herbs and red wine and is suggested to be a potential antiatherosclerotic drug due to its proposed hypolipidemic, anti-inflammatory and antioxidative properties. The aim of this study was to evaluate whether resveratrol protects against atherosclerosis development in APOE*3-Leiden.CETP (E3L.CETP) mice and adds to the antiatherogenic effect of mild statin treatment, currently the most widely used antiatherogenic therapy. E3L.CETP mice were fed a cholesterol-rich diet without (control) or with resveratrol (0.01% w/w), atorvastatin (0.0027% w/w) or both for 14 weeks. During the study plasma lipid, inflammatory and oxidative stress parameters were determined. Resveratrol reduced atherosclerotic lesion area (-52%) in the aortic root, comparable to atorvastatin (-40%) and the combination of both drugs (-47%). The collagen/macrophage ratio in the atherosclerotic lesion, a marker of plaque stability, was increased by resveratrol (+108%), atorvastatin (+124%) and the combination (+154%). Resveratrol decreased plasma cholesterol levels (-19%) comparable to atorvastatin (-19%) and the combination (-22%), which was completely confined to (very)low-density lipoprotein cholesterol levels in all groups. Post hoc analyses showed that the antiatherogenic effect of atorvastatin could be explained by cholesterol lowering, while the antiatherosclerotic effect of resveratrol could be attributed to factors additional to cholesterol lowering. Markers of inflammation and oxidative stress were not different, but resveratrol improved macrophage function. We conclude that resveratrol potently reduces atherosclerosis development and induces a more stable lesion phenotype in E3L.CETP mice. However, under the experimental conditions tested, resveratrol does not add to the antiatherogenic effect of atorvastatin.

Keywords: 3-hydroxy-3-methylglutaryl coenzyme A reductase; 8-iso-PGF(2α); APOE*3-Leiden transgenic; Atherosclerosis; CETP; CXCL1; E3L; HMG-CoA reductase; IL; Ig; Inflammation; LPS; Lipids; MCP-1; Oxidative stress; RT-PCR; Resveratrol; SMC; Statin; TG; WTD; Western-type diet; chemokine (C-X-C motif) ligand-1; cholesteryl ester transfer protein cox1/-2, cyclooxygenase-1/-2; immunoglobulin; interleukin; isoprostane 15(S)-8-iso-prostaglandin F(2α); lectin-like oxidized low-density lipoprotein receptor-1; lipopolysaccharide; lox-1; manganese superoxide dismutase; mnsod; monocyte chemoattractant protein-1; oxLDL; oxidized LDL; paraoxonase-1; pon1; real-time polymerase chain reaction; sE-selectin; smooth muscle cell; soluble E-selectin; triglycerides.