Targeting LDL aggregation decreases atherosclerotic lipid burden in a humanized mouse model of familial hypercholesterolemia: Crucial role of ApoB100 conformational stabilization
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. (Universidad de Zaragoza) ; Prades, R. ; Escola-Gil, J.C. ; Llorente-Cortés, V.
Resumen: Background and aims: 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.
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 mi-croscopy. 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 pro-tected 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.
Idioma: Inglés
DOI: 10.1016/j.atherosclerosis.2024.118630
Año: 2024
Publicado en: Atherosclerosis (2024), 118630 [17 pp.]
ISSN: 0021-9150
Factor impacto JCR: 5.7 (2024)
Categ. JCR: PERIPHERAL VASCULAR DISEASE rank: 11 / 98 = 0.112 (2024) - Q1 - T1
Categ. JCR: CARDIAC & CARDIOVASCULAR SYSTEMS rank: 37 / 230 = 0.161 (2024) - Q1 - T1
Factor impacto SCIMAGO: 1.762 - Cardiology and Cardiovascular Medicine (Q1)
Financiación: info:eu-repo/grantAgreement/ES/FIS/PI21-01523
Financiación: info:eu-repo/grantAgreement/ES/MCIU/FPU21/01173
Financiación: info:eu-repo/grantAgreement/ES/MCIU/FPU22/01888
Financiación: info:eu-repo/grantAgreement/ES/MINECO/RED2018-102799-T
Tipo y forma: Article (Published version)
Área (Departamento): Area Medicina (Dpto. Medicina, Psiqu. y Derm.)
You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. You may not use the material for commercial purposes.
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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 mi-croscopy. 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 pro-tected 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.
Idioma: Inglés
DOI: 10.1016/j.atherosclerosis.2024.118630
Año: 2024
Publicado en: Atherosclerosis (2024), 118630 [17 pp.]
ISSN: 0021-9150
Factor impacto JCR: 5.7 (2024)
Categ. JCR: PERIPHERAL VASCULAR DISEASE rank: 11 / 98 = 0.112 (2024) - Q1 - T1
Categ. JCR: CARDIAC & CARDIOVASCULAR SYSTEMS rank: 37 / 230 = 0.161 (2024) - Q1 - T1
Factor impacto SCIMAGO: 1.762 - Cardiology and Cardiovascular Medicine (Q1)
Financiación: info:eu-repo/grantAgreement/ES/FIS/PI21-01523
Financiación: info:eu-repo/grantAgreement/ES/MCIU/FPU21/01173
Financiación: info:eu-repo/grantAgreement/ES/MCIU/FPU22/01888
Financiación: info:eu-repo/grantAgreement/ES/MINECO/RED2018-102799-T
Tipo y forma: Article (Published version)
Área (Departamento): Area Medicina (Dpto. Medicina, Psiqu. y Derm.)
You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. You may not use the material for commercial purposes. Exportado de SIDERAL (2025-10-17-14:30:25)
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