Resveratrol protects against atherosclerosis, but does not add to the antiatherogenic effect of atorvastatin, in APOE3-Leiden.CETP mice

• Published in: The Journal of nutritional biochemistry Vol. 24; no. 8; pp. 1423 - 1430
• Main Authors: Berbée, Jimmy F.P, Wong, Man C, Wang, Yanan, van der Hoorn, José W.A, Khedoe, Padmini P.S.J, van Klinken, Jan B, Mol, Isabel M, Hiemstra, Pieter S, Tsikas, Dimitrios, Romijn, Johannes A, Havekes, Louis M, Princen, Hans M.G, Rensen, Patrick C.N
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2013
• Subjects: administration & dosage; Animals; antioxidant activity; Atherosclerosis; Atherosclerosis - drug therapy; Atherosclerosis - pathology; Atorvastatin Calcium; Biomarkers; Biomarkers - blood; blood; blood lipids; cholesterol; Cholesterol, Dietary; Cholesterol, Dietary - administration & dosage; Cholesterol, LDL; Cholesterol, LDL - blood; collagen; diet; drug effects; Drug Synergism; drug therapy; drugs; Female; Heptanoic Acids; Heptanoic Acids - pharmacology; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Inflammation; Inflammation - drug therapy; Lipids; low density lipoprotein; medicinal plants; Mice; Mice, Transgenic; Oxidative stress; Oxidative Stress - drug effects; pathology; pharmacology; phenotype; Pyrroles; Pyrroles - pharmacology; red wines; Resveratrol; Statin; Stilbenes; Stilbenes - pharmacology; therapeutics; CETP; Oxidative stress; MCP-1; IL; WTD; SMC; sE-selectin; Lipids; CXCL1; Inflammation; Statin; LPS; TG; mnsod; HMG-CoA reductase; pon1; RT-PCR; Atherosclerosis; Resveratrol; oxLDL; Ig; 8-iso-PGF2α; E3L; lox-1; chemokine (C-X-C motif) ligand-1; soluble E-selectin; monocyte chemoattractant protein-1; 8-iso-PGF(2α); manganese superoxide dismutase; oxidized LDL; 3-hydroxy-3-methylglutaryl coenzyme A reductase; interleukin; smooth muscle cell; cholesteryl ester transfer protein cox1/-2, cyclooxygenase-1/-2; immunoglobulin; real-time polymerase chain reaction; triglycerides; isoprostane 15(S)-8-iso-prostaglandin F(2α); paraoxonase-1; Western-type diet; lectin-like oxidized low-density lipoprotein receptor-1; APOE3-Leiden transgenic; lipopolysaccharide
• ISSN: 0955-2863; 1873-4847; 1873-4847
• DOI: 10.1016/j.jnutbio.2012.11.009

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.