000150490 001__ 150490 000150490 005__ 20251017144638.0 000150490 0247_ $$2doi$$a10.1016/j.atherosclerosis.2024.118630 000150490 0248_ $$2sideral$$a142689 000150490 037__ $$aART-2024-142689 000150490 041__ $$aeng 000150490 100__ $$aBenitez-Amaro, A. 000150490 245__ $$aTargeting LDL aggregation decreases atherosclerotic lipid burden in a humanized mouse model of familial hypercholesterolemia: Crucial role of ApoB100 conformational stabilization 000150490 260__ $$c2024 000150490 5060_ $$aAccess copy available to the general public$$fUnrestricted 000150490 5203_ $$aBackground 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. 000150490 536__ $$9info:eu-repo/grantAgreement/ES/FIS/PI21-01523$$9info:eu-repo/grantAgreement/ES/MCIU/FPU21/01173$$9info:eu-repo/grantAgreement/ES/MCIU/FPU22/01888$$9info:eu-repo/grantAgreement/ES/MINECO/RED2018-102799-T 000150490 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc$$uhttps://creativecommons.org/licenses/by-nc/4.0/deed.es 000150490 590__ $$a5.7$$b2024 000150490 592__ $$a1.762$$b2024 000150490 591__ $$aPERIPHERAL VASCULAR DISEASE$$b11 / 98 = 0.112$$c2024$$dQ1$$eT1 000150490 593__ $$aCardiology and Cardiovascular Medicine$$c2024$$dQ1 000150490 591__ $$aCARDIAC & CARDIOVASCULAR SYSTEMS$$b37 / 230 = 0.161$$c2024$$dQ1$$eT1 000150490 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000150490 700__ $$aGarcia, E. 000150490 700__ $$aLa Chica Lhoëst, M.T. 000150490 700__ $$aMartínez, A. 000150490 700__ $$aBorràs, C. 000150490 700__ $$aTondo, M. 000150490 700__ $$aCéspedes, M.V. 000150490 700__ $$aCaruana, P. 000150490 700__ $$aPepe, A. 000150490 700__ $$aBochicchio, B. 000150490 700__ $$aCenarro, A. 000150490 700__ $$0(orcid)0000-0001-7043-0952$$aCiveira, F.$$uUniversidad de Zaragoza 000150490 700__ $$aPrades, R. 000150490 700__ $$aEscola-Gil, J.C. 000150490 700__ $$aLlorente-Cortés, V. 000150490 7102_ $$11007$$2610$$aUniversidad de Zaragoza$$bDpto. Medicina, Psiqu. y Derm.$$cArea Medicina 000150490 773__ $$g(2024), 118630 [17 pp.]$$pAtherosclerosis$$tAtherosclerosis$$x0021-9150 000150490 8564_ $$s12686867$$uhttps://zaguan.unizar.es/record/150490/files/texto_completo.pdf$$yVersión publicada 000150490 8564_ $$s2328887$$uhttps://zaguan.unizar.es/record/150490/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000150490 909CO $$ooai:zaguan.unizar.es:150490$$particulos$$pdriver 000150490 951__ $$a2025-10-17-14:30:25 000150490 980__ $$aARTICLE