Τίτλος:
Statins’ Withdrawal Induces Atherosclerotic Plaque Destabilization in Animal Model—A “Rebound” Stimulation of Inflammation
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Background: To evaluate the impact of atorvastatin discontinuation on the progression and stability of atherosclerotic plaques in a valid animal model of atherosclerosis. Methods: Seventy ApoE−/− male mice fed with high-fat diet were randomly assigned into: (1) long-term intervention groups: (i) ATL, received atorvastatin for 12 weeks, (ii) CO-12W, control received vehicle for 12 weeks, (iii) ATW-6W, received atorvastatin for 6 weeks which was withdrawn for another 6 weeks. (2) Short-term intervention groups: (i) ATS received atorvastatin for 6 weeks, (ii) CO-6W, control receiving vehicle for 6 weeks, (iii) ATW-3D, ATW-7D, received atorvastatin for 6 weeks which was withdrawn for 3 days and 7 days, respectively. Daily dosage of atorvastatin was 20 mg/kg. Mice were killed and aortic samples were obtained for histological evaluation. Results: Long-term atorvastatin treatment (ATL) induced atherosclerosis regression and stabilization compared to control (P <.05). Atorvastatin’s withdrawal was associated with acute (ATW-3D) reduction in connective tissue and collagen contents within plaques compared to ATS (P <.05). Those changes were almost restored after a while (ATW-7D) and started appearing again after longer cessation (ATW-6W). Moreover, atorvastatin withdrawal induced shortly (ATW-3D) a peak in inflammatory markers (macrophages, MCP-1, tumor necrosis factor-α) and matrix metalloproteinases (MMP-3, MMP-9) concentrations within plaques, which sustained but to a lesser extent along time (ATW-7D, ATW-6W). Conclusion: Short-term withdrawal of atorvastatin seems to compromise its antiatherosclerotic effects, leading to an unstable phenotype of the atherosclerotic lesions and a rebound increase in inflammatory mediators. The clinical relevance of our findings requires further investigation. © The Author(s) 2019.
Συγγραφείς:
Stasinopoulou, M.
Kadoglou, N.P.E.
Christodoulou, E.
Paronis, E.
Kostomitsopoulos, N.G.
Valsami, G.
Liapis, C.D.
Kakisis, J.
Περιοδικό:
Journal of Cardiovascular Pharmacology and Therapeutics
Εκδότης:
SAGE Publications Ltd
Λέξεις-κλειδιά:
atorvastatin; biological marker; collagen; gelatinase B; hydroxymethylglutaryl coenzyme A reductase inhibitor; monocyte chemotactic protein 1; stromelysin; tumor necrosis factor; antiinflammatory agent; atorvastatin; autacoid; collagen; hydroxymethylglutaryl coenzyme A reductase inhibitor, animal experiment; animal model; animal tissue; antiinflammatory activity; aortic tissue; apolipoprotein E knockout mouse; Article; atherosclerotic plaque; concentration (parameter); connective tissue; controlled study; drug effect; drug withdrawal; immunohistochemistry; lipid diet; macrophage; male; mouse; nonhuman; priority journal; random sample; tissue section; animal; aorta; aortic disease; atherosclerosis; disease exacerbation; disease model; drug administration; drug effect; genetics; human; metabolism; pathology; rupture; signal transduction; time factor, Animals; Anti-Inflammatory Agents; Aorta; Aortic Diseases; Atherosclerosis; Atorvastatin; Collagen; Disease Models, Animal; Disease Progression; Drug Administration Schedule; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation Mediators; Mice, Knockout, ApoE; Plaque, Atherosclerotic; Rupture, Spontaneous; Signal Transduction; Time Factors
DOI:
10.1177/1074248419838499
