Title
Alirocumab inhibits atherosclerosis, improves the plaque morphology, and enhances the effects of a statin
Author
Kühnast, S.
van der Hoorn, J.W.A.
Pieterman, E.J.
van den Hoek, A.M.
Sasiela, W.J.
Gusarova, V.
Peyman, A.
Schäfer, H.L.
Schwahn, U.
Jukema, J.W.
Princen, H.M.G.
Publication year
2014
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a potential novel strategy for treatment of CVD. Alirocumab is a fully human PCSK9 monoclonal antibody in phase 3 clinical development. We evaluated the antiatherogenic potential of alirocumab in APOE∗3Leiden. CETP mice. Mice received a Western-type diet and were treated with alirocumab (3 or 10 mg/kg, weekly subcutaneous dosing) alone and in combination with atorvastatin (3.6 mg/kg/d) for 18 weeks. Alirocumab alone dose-dependently decreased total cholesterol (-37%; -46%, P < 0.001) and TGs (-36%; -39%, P < 0.001) and further decreased cholesterol in combination with atorvastatin (-48%; -58%, P < 0.001). Alirocumab increased hepatic LDL receptor protein levels but did not affect hepatic cholesterol and TG content. Fecal output of bile acids and neutral sterols was not changed. Alirocumab dose-dependently decreased atherosclerotic lesion size (-71%; -88%, P < 0.001) and severity and enhanced these effects when added to atorvastatin (-89%; -98%, P < 0.001). Alirocumab reduced monocyte recruitment and improved the lesion composition by increasing the smooth muscle cell and collagen content and decreasing the macrophage and necrotic core content. Alirocumab dose-dependently decreases plasma lipids and, as a result, atherosclerosis development, and it enhances the beneficial effects of atorvastatin in APOE∗3Leiden.CETP mice. In addition, alirocumab improves plaque morphology. Chemicals/CAS: alirocumab, 1245916-14-6; atorvastatin, 134523-00-5, 134523-03-8; cholesterol, 57-88-5; collagen, 9007-34-5
Subject
ELSS - Earth, Life and Social Sciences
Life
Healthy Living
Biomedical Innovation
3Leiden.CETP mice
APOE
Atorvastatin
Proprotein convertase subtilisin/kexin type 9
Alirocumab
Apolipoprotein E
Atorvastatin
Bile acid
Cholesterol
Collagen
Low density lipoprotein receptor
Sterol
Triacylglycerol
Animal experiment
Animal model
Atherosclerosis
Atherosclerotic plaque
Controlled study
Disease severity
Dose response
Drug effect
Drug potentiation
Drug safety
Fat content
Female
Lipid blood level
Monocyte
Monotherapy
Mouse
Nonhuman
Protein degradation
Smooth muscle fiber
MHR - Metabolic Health Research
To reference this document use:
http://resolver.tudelft.nl/uuid:17ce4754-8fa8-4e08-b529-0e07e5ec7fb3
DOI
https://doi.org/10.1194/jlr.m051326
TNO identifier
517666
ISSN
0022-2275
Source
Journal of Lipid Research, 55 (55), 2103-2112
Bibliographical note
Manufacturers: Regeneron Funding Details: Roche
Document type
article