Targeting LDL aggregation decreases atherosclerotic lipid burden in a humanized mouse model of familial hypercholesterolemia: Crucial role of ApoB100 conformational stabilization.

Autor: Benitez-Amaro A; Institute of Biomedical Research of Barcelona (IIBB)-Spanish National Research Council (CSIC), 08036, Barcelona, Spain; Institut d'Investigacions Biomèdiques IIB Sant Pau, 08041, Barcelona, Spain., Garcia E; Institute of Biomedical Research of Barcelona (IIBB)-Spanish National Research Council (CSIC), 08036, Barcelona, Spain; Institut d'Investigacions Biomèdiques IIB Sant Pau, 08041, Barcelona, Spain; Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain., La Chica Lhoëst MT; Institute of Biomedical Research of Barcelona (IIBB)-Spanish National Research Council (CSIC), 08036, Barcelona, Spain; Institut d'Investigacions Biomèdiques IIB Sant Pau, 08041, Barcelona, Spain; Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain., Martínez A; Institute of Biomedical Research of Barcelona (IIBB)-Spanish National Research Council (CSIC), 08036, Barcelona, Spain; Institut d'Investigacions Biomèdiques IIB Sant Pau, 08041, Barcelona, Spain., Borràs C; Institut de Recerca de l'Hospital Santa Creu i Sant Pau, Institut d'Investigacions Biomèdiques IIB Sant Pau, 08041, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029, Madrid, Spain., Tondo M; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029, Madrid, Spain; Department of Clinical Biochemistry, Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, 08041, Barcelona, Spain., Céspedes MV; Grup d'Oncologia Ginecològica i Peritoneal, Institut de Recerca Sant Pau, Hospital de la Santa Creu i Sant Pau, 08041, Barcelona, Spain; Universitat de Barcelona (UB), 08007, Barcelona, Spain., Caruana P; Grup d'Oncologia Ginecològica i Peritoneal, Institut de Recerca Sant Pau, Hospital de la Santa Creu i Sant Pau, 08041, Barcelona, Spain; Universitat de Barcelona (UB), 08007, Barcelona, Spain., Pepe A; Laboratory of Bioinspired Materials, Department of Science, University of Basilicata, Potenza, Italy., Bochicchio B; Laboratory of Bioinspired Materials, Department of Science, University of Basilicata, Potenza, Italy., Cenarro A; Hospital Universitario Miguel Servet, IIS Aragón, Instituto Aragonés de Ciencias de la Salud, Universidad de Zaragoza, Zaragoza, Spain; CIBER de Enfermedades Cardiovasculares CIBERCV, Institute of Health Carlos III, 28029, Madrid, Spain., Civeira F; Hospital Universitario Miguel Servet, IIS Aragón, Instituto Aragonés de Ciencias de la Salud, Universidad de Zaragoza, Zaragoza, Spain; CIBER de Enfermedades Cardiovasculares CIBERCV, Institute of Health Carlos III, 28029, Madrid, Spain., Prades R; Iproteos S.L., Barcelona Science Park (PCB), Barcelona, Spain., Escola-Gil JC; Institut de Recerca de l'Hospital Santa Creu i Sant Pau, Institut d'Investigacions Biomèdiques IIB Sant Pau, 08041, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029, Madrid, Spain., Llorente-Cortés V; Institute of Biomedical Research of Barcelona (IIBB)-Spanish National Research Council (CSIC), 08036, Barcelona, Spain; Institut d'Investigacions Biomèdiques IIB Sant Pau, 08041, Barcelona, Spain; CIBER de Enfermedades Cardiovasculares CIBERCV, Institute of Health Carlos III, 28029, Madrid, Spain. Electronic address: cllorente@santpau.cat.
Jazyk: angličtina
Zdroj: Atherosclerosis [Atherosclerosis] 2024 Oct 19, pp. 118630. Date of Electronic Publication: 2024 Oct 19.
DOI: 10.1016/j.atherosclerosis.2024.118630
Abstrakt: Background and Aims: Low-density lipoprotein (LDL) aggregation is nowadays considered a therapeutic target in atherosclerosis. DP3, the retro-enantio version of the sequence Gly 1127 -Cys 1140 of LRP1, efficiently inhibits LDL aggregation and foam cell in vitro formation. Here, we investigate whether DP3 modulates atherosclerosis in a humanized ApoB100, LDL receptor (LDLR) knockout mice (Ldlr -/- hApoB100 Tg) and determine the potential LDL-related underlying mechanisms.
Methods: Tg mice were fed an HFD for 21 days to induce atherosclerosis and then randomized into three groups that received a daily subcutaneous administration (10 mg/kg) of i) vehicle, ii) DP3 peptide, or iii) a non-active peptide (IP321). The in vivo biodistribution of a fluorescent-labeled peptide version (TAMRA-DP3), and its colocalization with ApoB100 in the arterial intima, was analyzed by imaging system (IVIS) and confocal microscopy. Heart aortic roots were used for atherosclerosis detection and quantification. LDL functionality was analyzed by biochemical, biophysical, molecular, and cellular studies.
Results: Intimal neutral lipid accumulation in the aortic root was reduced in the DP3-treated group as compared to control groups. ApoB100 in LDLs from the DP3 group exhibited an increased percentage of α-helix secondary structures and decreased immunoreactivity to anti-ApoB100 antibodies. LDL from DP3-treated mice were protected against passive and sphingomyelinase (SMase)-induced aggregation, although they still experienced SMase-induced sphingomyelin phospholysis. In patients with familial hypercholesterolemia (FH), DP3 efficiently inhibited both SMase-induced phospholysis and aggregation.
Conclusions: DP3 peptide administration inhibits atherosclerosis by preserving the α-helix secondary structures of ApoB100 in a humanized ApoB100 murine model that mimicks the hallmark of human hypercholesterolemia.
Competing Interests: Declaration of competing interest All authors have read and approved submission of the manuscript and the manuscript has not been published and is not being considered for publication elsewhere in whole or part in any language except as an abstract. None of the authors have any conflict of interest with the publication of the manuscript.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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