Publication
Title
Cholesterol-independent effects of atorvastatin prevent cardiovascular morbidity and mortality in a mouse model of atherosclerotic plaque rupture
Author
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 (Fbn1C1039G +/−). These mice develop exacerbated atherosclerosis and spontaneous plaque ruptures, accompanied by myocardial infarctions (MI) and sudden death. ApoE−/− Fbn1C1039G +/− mice were fed a Western diet (WD). At week 10 of WD, mice were divided in a control (WD), atorvastatin (10 mg/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.
Language
English
Source (journal)
Vascular pharmacology. - New York, N.Y.
Publication
New York, N.Y. : 2016
ISSN
1537-1891
Volume/pages
80(2016), p. 50-58
ISI
000374208900006
Full text (Publisher's DOI)
Full text (open access)
UAntwerpen
Faculty/Department
Research group
[E?say:metaLocaldata.cgzprojectinf]
Optimization and validation of a mouse model of atherosclerotic plaque rupture.
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 19.02.2016
Last edited 13.10.2017
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