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Alirocumab inhibits atherosclerosis, improves the plaque morphology, and enhances the effects of a statin

Author: Kühnast, S. · Hoorn, J.W.A. van der · Pieterman, E.J. · Hoek, A.M. van den · Sasiela, W.J. · Gusarova, V. · Peyman, A. · Schäfer, H.L. · Schwahn, U. · Jukema, J.W. · Princen, H.M.G.
Type:article
Date:2014
Source:Journal of Lipid Research, 10, 55, 2103-2112
Identifier: 517666
doi: doi:10.1194/jlr.M051326
Keywords: Biology · 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 · Biomedical Innovation · Healthy Living · Life · MHR - Metabolic Health Research · ELSS - Earth, Life and Social Sciences

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