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

Low-density lipoprotein (LDL) aggregation is nowadays considered a therapeutic target in atherosclerosis. DP3, the retro-enantio version of the sequence Gly1127-Cys1140 of LRP1, efficiently inhibits LDL aggregation and foam cell in vitro formation. Here, we investigate whether DP3 modulates atherosc...

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Published in:Atherosclerosis 2024-10, p.118630, Article 118630
Main Authors: Benitez-Amaro, A., Garcia, E., La Chica Lhoëst, M.T., Martínez, A., Borràs, C., Tondo, M., Céspedes, M.V., Caruana, P., Pepe, A., Bochicchio, B., Cenarro, A., Civeira, F., Prades, R., Escola-Gil, J.C., Llorente-Cortés, V.
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Language:English
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Summary:Low-density lipoprotein (LDL) aggregation is nowadays considered a therapeutic target in atherosclerosis. DP3, the retro-enantio version of the sequence Gly1127-Cys1140 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. 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. 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. 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. [Display omitted] •DP3 peptide based on the sequence P3 (Gly1127-Cys1140) of LRP1 preserves ApoB100 conformation in vivo.•ApoB100 stabilization blocks passive and SMase-induced LDL aggregation.•DP3 peptide reduces atherosclerosis in a model resembling human familial hypercholesterolemia.
ISSN:0021-9150
1879-1484
1879-1484
DOI:10.1016/j.atherosclerosis.2024.118630