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

IF 8.4 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS JACC: Basic to Translational Science Pub Date : 2024-10-01 DOI:10.1016/j.jacbts.2024.06.008

Carla Borràs MSc , Marina Canyelles PhD , Josefa Girona PhD , Daiana Ibarretxe MD, PhD , David Santos BS , Giovanna Revilla PhD , Vicenta Llorente-Cortes PhD , Noemí Rotllan PhD , Petri T. Kovanen MD, PhD , Matti Jauhiainen PhD , Miriam Lee-Rueckert PhD , Luis Masana MD, PhD , Francisco Arrieta MD, PhD , Javier Martínez-Botas PhD , Diego Gómez-Coronado PhD , Josep Ribalta PhD , Mireia Tondo PhD , Francisco Blanco-Vaca MD, PhD , Joan Carles Escolà-Gil PhD

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Abstract

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.

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PCSK9 抗体治疗特异性地增强了杂合子家族性高胆固醇血症患者巨噬细胞特异性胆固醇逆向转运途径的功能

我们研究了丙蛋白转化酶亚基酶/kexin 9型（PCSK9）抗体恢复杂合子家族性高胆固醇血症（FH）患者巨噬细胞胆固醇外流以及增强小鼠巨噬细胞特异性胆固醇逆向转运途径的潜力。对 FH 患者血浆中巨噬细胞衍生胆固醇分布的分析表明，使用 PCSK9 抑制剂治疗后，低密度脂蛋白（LDL）颗粒所含放射性标记胆固醇较少，而高密度脂蛋白颗粒所含放射性标记胆固醇较多。在表达人类 APOB100 的杂合子低密度脂蛋白受体缺陷小鼠体内，PCSK9 抗体可促进巨噬细胞衍生胆固醇和低密度脂蛋白衍生胆固醇转移到粪便中。PCSK9抑制剂是杂合子FH患者巨噬细胞特异性胆固醇逆向转运途径的积极调节剂。

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来源期刊

JACC: Basic to Translational Science CARDIAC & CARDIOVASCULAR SYSTEMS-

CiteScore

14.20

自引率

1.00%

发文量

161

审稿时长

16 weeks

期刊介绍： JACC: Basic to Translational Science is an open access journal that is part of the renowned Journal of the American College of Cardiology (JACC). It focuses on advancing the field of Translational Cardiovascular Medicine and aims to accelerate the translation of new scientific discoveries into therapies that improve outcomes for patients with or at risk for Cardiovascular Disease. The journal covers thematic areas such as pre-clinical research, clinical trials, personalized medicine, novel drugs, devices, and biologics, proteomics, genomics, and metabolomics, as well as early phase clinical trial methodology.