Rosuvastatin reduces atherosclerosis development beyond and independent of its plasma cholesterol-lowering effect in APOE*3-Leiden transgenic mice: Evidence for antiinflammatory effects of rosuvastatin
article
Background - Statins can exert anti-inflammatory antiatherosclerotic effects through an anti-inflammatory action, independent of lowering cholesterol. We addressed the question whether the anti-inflammatory activities of statins can reduce atherosclerosis beyond the reduction achieved by cholesterol lowering per se. Methods and Results - Two groups of 20 female APOE*3-Leiden mice received either a high-cholesterol diet (HC) or a high-cholesterol diet supplemented with 0.005% (wt/wt) rosuvastatin (HC+R). The HC diet alone resulted in a plasma cholesterol concentration of 18.9±1.4 mmol/L, and administration of rosuvastatin lowered plasma cholesterol to 14.1±0.7 mmol/L. In a separate low-cholesterol (LC) control group, the dietary cholesterol intake was reduced, which resulted in plasma cholesterol levels that were comparable to the HC+R group (13.4±0.8 mmol/L). Atherosclerosis in the aortic root area was quantified after 24 weeks. As compared with the HC group, the LC group had a 62% (P<0.001) reduction in cross-sectional lesion area. When compared with the LC group, the HC+R group showed a further decrease in cross-sectional lesion area (80%, P<0.001), size of individual lesions (63%, P<0.05), lesion number (58%, P<0.001), monocyte adherence (24%, P<0.05), and macrophage-containing area (60%, P<0.001). Furthermore, rosuvastatin specifically suppressed the expression of the inflammation parameters MCP-1 and TNF-α in the vessel wall and lowered plasma concentrations of serum amyloid A and fibrinogen, independent of its cholesterol-lowering effect. Conclusions - Rosuvastatin reduces atherosclerosis beyond and independent of the reduction achieved by cholesterol lowering alone. This additional beneficial effect of rosuvastatin may be explained, at least partly, by its antiinflammatory activity. Chemicals/CAS: amyloid A protein, 59165-71-8; fibrinogen, 9001-32-5; rosuvastatin, 147098-18-8, 147098-20-2; cholesterol, 57-88-5; fluorobenzene, 2367-82-0, 327-54-8, 363-72-4, 367-23-7, 372-38-3, 462-06-6, 540-36-3; lipid, 66455-18-3; Anti-Inflammatory Agents; apolipoprotein E3 (Leidein); Apolipoprotein E3; Apolipoproteins E; Cholesterol, 57-88-5; Cytokines; Fluorobenzenes; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Lipoproteins; Pyrimidines; rosuvastatin, 287714-41-4; Sulfonamides
Topics
Biomedical ResearchCell adhesion moleculesInhibitorsAmyloid A proteinCell adhesion moleculeFibrinogenMonocyte chemotactic protein 1RosuvastatinStatine derivativeTumor necrosis factor alphaAntiinflammatory agentApolipoprotein EApolipoprotein E3 (Leidein)CytokineFluorobenzeneHydroxymethylglutaryl coenzyme A reductase inhibitorLipidLipoproteinPyrimidine derivativeSulfonamideAnimal cellAnimal experimentAnimal modelAnimal tissueAorta rootCell adhesionCholesterol blood levelCholesterol dietControlled studyInflammationMonocyteMouseNonhumanNucleotide sequenceTransgenic mouseBloodDrug effectGeneticsImmunologyMetabolismPathologyAnimalsAnti-Inflammatory AgentsAortaApolipoprotein E3Apolipoproteins EArteriosclerosisCell AdhesionCholesterolCytokinesFemaleFluorobenzenesHydroxymethylglutaryl-CoA Reductase InhibitorsLipidsLipoproteinsMacrophagesMiceMice, TransgenicMonocytesPyrimidinesSulfonamides
TNO Identifier
237283
ISSN
00097322
Source
Circulation, 108(11), pp. 1368-1374.
Pages
1368-1374
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