title: Cholesterol-independent effects of atorvastatin prevent cardiovascular morbidity and mortality in a mouse model of atherosclerotic plaque rupture.
abstract: Because cholesterol-independent effects of statins are difficult to determine in patients, we studied these pleiotropic effects in apolipoprotein E-deficient (ApoE(-/-)) mice with a mutation in the fibrillin-1 gene (Fbn1(C1039G+/-)). These mice develop exacerbated atherosclerosis and spontaneous plaque ruptures, accompanied by myocardial infarctions (MI) and sudden death. ApoE(-/-)Fbn1(C1039G+/-) mice were fed a Western diet (WD). At week 10 of WD, mice were divided in a control (WD), atorvastatin (10mg/kg/day + WD) and cholesterol withdrawal group (cholW, normal chow). The latter was included to compare the effects of atorvastatin with dietary lipid lowering. Fifteen weeks later, the mice were sacrificed. CholW, but not atorvastatin, reduced plasma cholesterol. Survival increased from 50% to 90% both in cholW and atorvastatin treated mice. CholW as well as atorvastatin treatment increased plaque collagen and fibrous cap thickness, but they did not affect the amount of plaque macrophages and T cells. MMP-2 and MMP-9 activity was significantly lower and the expression of MMP-12, TNF-α and IL-1β was strongly reduced in both treatment groups. Blood monocytes and neutrophils returned to baseline levels (ApoE(-/-) mice before the onset of atherosclerosis). Importantly, atorvastatin but not cholW significantly reduced coronary stenosis (from 50 to 28%) and the occurrence of MI (from 43 to 10%). In conclusion, independent of cholesterol lowering, atorvastatin significantly reduced mortality, plaque vulnerability and inflammation to the same extent as cholW. In addition, atorvastatin but not cholW reduced coronary stenosis and the occurrence of MI. These data unequivocally illustrate the significance of the pleiotropic effects of atorvastatin in the prevention of cardiovascular morbidity and mortality.
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium. Electronic address: lynn.roth@uantwerpen.be.
authors.forename: Lynn
authors.initials: L
authors.lastname: Roth
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
authors.forename: Miche
authors.initials: M
authors.lastname: Rombouts
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
authors.forename: Dorien M
authors.initials: DM
authors.lastname: Schrijvers
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Martinet
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
authors.forename: Guido R Y
authors.initials: GR
authors.lastname: De Meyer
mesh_terms: D000821:Animal Feed; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000235:genetics; D000069059:Atorvastatin / Q000008:administration & dosage / Q000627:therapeutic use*; D002784:Cholesterol / Q000097:blood* / Q000172:deficiency; D004195:Disease Models, Animal; D005260:Female; D000071838:Fibrillin-1 / Q000235:genetics; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D053208:Kaplan-Meier Estimate; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000097:blood / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D016019:Survival Analysis; D054392:Adipokines
chemical_list: D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D000069059:Atorvastatin; D002784:Cholesterol; D000071838:Fibrillin-1; C000605724:Fbn1 protein, mouse; D054392:Adipokines
keywords: Coronary stenosis; Inflammatory cytokines; Matrix metalloproteinases; Myocardial infarction; Pleiotropic effects