PCSK9 Antibodies Treatment Specifically Enhances the Macrophage-specific Reverse Cholesterol Transport Pathway in Heterozygous Familial Hypercholesterolemia.

We investigated the potential of proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies to restore macrophage cholesterol efflux in subjects with heterozygous familial hypercholesterolemia (FH) and to enhance the macrophage-specific reverse cholesterol transport pathway in mice. Analyses of macrophage-derived cholesterol distribution of plasma from FH patients revealed that low-density lipoprotein (LDL) particles contained less, and high-density lipoprotein particles contained more radiolabeled cholesterol after treatment with either PCSK9 inhibitor. PCSK9 antibodies facilitated the transfer of macrophage-derived cholesterol and LDL-derived cholesterol to feces exclusively in heterozygous LDL receptor-deficient mice expressing human APOB100. PCSK9 inhibitors act as positive regulators of the macrophage-specific reverse cholesterol transport pathway in individuals with heterozygous FH.
Competing Interests: This work was partly funded by the Instituto de Salud Carlos III and FEDER “Una manera de hacer Europa” grants PI2100140 (to Dr Blanco-Vaca and Dr Tondo), PI2101523 (to Dr Llorente-Cortes), PI2300232 (to Dr Canyelles and Dr Escolà-Gil), JR22/00003 (to Dr Canyelles), by the Ministerio de Ciencia e Innovación grant RTI2018-098113-B-I00 (to Dr Gómez-Coronado), by BBVA Foundation Ayudas a Equipos de Investigación 2019 to the project “Translational Molecular Imaging for detection of Cholesterol Entrapment in the Vasculature with 68Ga-labeled LRP1-derived peptides” (to Dr Llorente-Cortes) and grant 12/C/2015 from La Fundació la Marató TV3 (to Dr Masana and Dr Blanco-Vaca); the Jane and Aatos Erkko Foundation (to Dr Jauhiainen), and the Finnish Foundation for Cardiovascular Research (to Dr Jauhiainen). Ms Borràs was funded with a Formación de Profesorado Universitario grant FPU20/07440 from the Ministerio de Universidades. Dr Rotllan was funded by Agencia Estatal de Investigación (AEI/10.13039/501100011033) within the Subprograma Ramón y Cajal (RYC-201722879). CIBERDEM and CIBERCV are Instituto de Salud Carlos III projects. All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
(© 2024 The Authors.)