title: Alirocumab inhibits atherosclerosis, improves the plaque morphology, and enhances the effects of a statin.
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.
authors.affiliation: The Netherlands Organization of Applied Scientific Research (TNO) - Metabolic Health Research, Gaubius Laboratory, Leiden, The Netherlands Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Susan
authors.initials: S
authors.lastname: Kühnast
authors.affiliation: The Netherlands Organization of Applied Scientific Research (TNO) - Metabolic Health Research, Gaubius Laboratory, Leiden, The Netherlands Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: José W A
authors.initials: JW
authors.lastname: van der Hoorn
authors.affiliation: The Netherlands Organization of Applied Scientific Research (TNO) - Metabolic Health Research, Gaubius Laboratory, Leiden, The Netherlands.
authors.forename: Elsbet J
authors.initials: EJ
authors.lastname: Pieterman
authors.affiliation: The Netherlands Organization of Applied Scientific Research (TNO) - Metabolic Health Research, Gaubius Laboratory, Leiden, The Netherlands.
authors.forename: Anita M
authors.initials: AM
authors.lastname: van den Hoek
authors.affiliation: Regeneron Pharmaceuticals Inc., Tarrytown, NY.
authors.forename: William J
authors.initials: WJ
authors.lastname: Sasiela
authors.affiliation: Regeneron Pharmaceuticals Inc., Tarrytown, NY.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Gusarova
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany.
authors.forename: Anusch
authors.initials: A
authors.lastname: Peyman
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany.
authors.forename: Hans-Ludwig
authors.initials: HL
authors.lastname: Schäfer
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Schwahn
authors.affiliation: Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.affiliation: The Netherlands Organization of Applied Scientific Research (TNO) - Metabolic Health Research, Gaubius Laboratory, Leiden, The Netherlands.
authors.forename: Hans M G
authors.initials: HM
authors.lastname: Princen
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; C571059:alirocumab
keywords: APOE*3Leiden.CETP mice; atorvastatin; proprotein convertase subtilisin/kexin type 9