Targeting LDL aggregation decreases atherosclerotic lipid burden in a humanized mouse model of familial hypercholesterolemia: Crucial role of ApoB100 conformational stabilization
Por:
Benitez-Amaro, A, Garcia, E, Lhoëst, MTL, Martínez, A, Borrás, C, Tondo, M, Céspedes, MV, Caruana, P, Pepe, A, Bochicchio, B, Cenarro, A, Civeira, F, Prades, R, Escola-Gil, JC, Llorente-Cortés, V
Publicada:
1 nov 2025
Ahead of Print:
1 nov 2025
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 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 alpha-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 alpha-helix secondary structures of ApoB100 in a humanized ApoB100 murine model that mimicks the hallmark of human hypercholesterolemia.
Filiaciones:
Benitez-Amaro, A:
CSIC, Inst Biomed Res Barcelona, Barcelona 08036, Spain
Inst Invest Biomed St Pau, Barcelona 08041, Spain
Garcia, E:
CSIC, Inst Biomed Res Barcelona, Barcelona 08036, Spain
Inst Invest Biomed St Pau, Barcelona 08041, Spain
Univ Autonoma Barcelona, Barcelona 08193, Spain
Lhoëst, MTL:
CSIC, Inst Biomed Res Barcelona, Barcelona 08036, Spain
Inst Invest Biomed St Pau, Barcelona 08041, Spain
Univ Autonoma Barcelona, Barcelona 08193, Spain
Martínez, A:
CSIC, Inst Biomed Res Barcelona, Barcelona 08036, Spain
Inst Invest Biomed St Pau, Barcelona 08041, Spain
Borrás, C:
Inst Invest Biomed St Pau, Inst Recerca Hosp Santa Creu & St Pau, Barcelona 08041, Spain
CIBER Diabet & Enfermedades Metab Asociadas, Madrid 28029, Spain
Tondo, M:
CIBER Diabet & Enfermedades Metab Asociadas, Madrid 28029, Spain
Hosp Santa Creu & Sant Pau, Dept Clin Biochem, Barcelona 08041, Spain
Céspedes, MV:
Inst Recerca St Pau, Hosp Santa Creu & St Pau, Grup Oncol Ginecol & Peritoneal, Barcelona 08041, Spain
Univ Barcelona, Barcelona 08007, Spain
Caruana, P:
Inst Recerca St Pau, Hosp Santa Creu & St Pau, Grup Oncol Ginecol & Peritoneal, Barcelona 08041, Spain
Univ Barcelona, Barcelona 08007, Spain
Pepe, A:
Univ Basilicata, Dept Sci, Lab Bioinspired Mat, Potenza, Italy
Bochicchio, B:
Univ Basilicata, Dept Sci, Lab Bioinspired Mat, Potenza, Italy
Cenarro, A:
Univ Zaragoza, Hosp Univ Miguel Servet, IIS Arago, Inst Aragones Ciencias Salud, Zaragoza, Spain
Inst Hlth Carlos III, CIBER Enfermedades Cardiovasc, Madrid 28029, Spain
Civeira, F:
Univ Zaragoza, Hosp Univ Miguel Servet, IIS Arago, Inst Aragones Ciencias Salud, Zaragoza, Spain
Inst Hlth Carlos III, CIBER Enfermedades Cardiovasc, Madrid 28029, Spain
Prades, R:
Iproteos SL, Barcelona Sci Pk, Barcelona, Spain
Escola-Gil, JC:
Inst Invest Biomed St Pau, Inst Recerca Hosp Santa Creu & St Pau, Barcelona 08041, Spain
CIBER Diabet & Enfermedades Metab Asociadas, Madrid 28029, Spain
Llorente-Cortés, V:
CSIC, Inst Biomed Res Barcelona, Barcelona 08036, Spain
Inst Invest Biomed St Pau, Barcelona 08041, Spain
Inst Hlth Carlos III, CIBER Enfermedades Cardiovasc, Madrid 28029, Spain
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