Alirocumab inhibits atherosclerosis, improves the plaque morphology, and enhances the effects of a statin
article
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
Chemicals/CAS: alirocumab, 1245916-14-6; atorvastatin, 134523-00-5, 134523-03-8; cholesterol, 57-88-5; collagen, 9007-34-5
Topics
3Leiden.CETP miceAPOEAtorvastatinProprotein convertase subtilisin/kexin type 9AlirocumabApolipoprotein EAtorvastatinBile acidCholesterolCollagenLow density lipoprotein receptorSterolTriacylglycerolAnimal experimentAnimal modelAtherosclerosisAtherosclerotic plaqueControlled studyDisease severityDose responseDrug effectDrug potentiationDrug safetyFat contentFemaleLipid blood levelMonocyteMonotherapyMouseNonhumanProtein degradationSmooth muscle fiber
TNO Identifier
517666
ISSN
00222275
Source
Journal of Lipid Research, 55(10), pp. 2103-2112.
Pages
2103-2112