2024-03-29T02:01:21Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/2196662020-09-17T01:13:07Zcom_10261_105com_10261_1col_10261_358
2020-09-16T06:56:56Z
urn:hdl:10261/219666
Immunization with the Gly1127-Cys1140 amino acid sequence of the LRP1 receptor reduces atherosclerosis in rabbits. Molecular, immunohistochemical and nuclear imaging studies
Bornachea, Olga
Benitez-Amaro, Aleyda
Vea, Ángela
Nasarre, Laura
Gonzalo-Calvo, David de
Escolà-Gil, Joan Carles
Cedó, Lídia
Iborra, Antoni
Martínez-Martínez, Laura
Juárez, Cándido
Cámara, Juan Antonio
Espinet, Carina
Borrell-Pages, Maria
Badimón Maestro, Lina
Castell, Joan
Llorente-Cortés, Vicenta
Fundació La Marató de TV3
Instituto de Salud Carlos III
Ministerio de Economía y Competitividad (España)
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (España)
Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares (España)
Generalitat de Catalunya
LRP1 (CR9)
Atherosclerosis
LDL
Vascular cholesteryl esters
NF-kB
TNFR1
18F-FDG-PET/CT
Doppler ultrasonography
Inflammation
Background: The LRP1 (CR9) domain and, in particular, the sequence Gly1127-Cys1140 (P3) plays a critical role in the binding and internalization of aggregated LDL (agLDL). We aimed to evaluate whether immunization with P3 reduces high-fat diet (HFD)-induced atherosclerosis.
Methods: Female New Zealand White (NZW) rabbits were immunized with a primary injection and four reminder doses (R1-R4) of IrP (irrelevant peptide) or P3 conjugated to the carrier. IrP and P3-immunized rabbits were randomly divided into a normal diet group and a HFD-fed group. Anti-P3 antibody levels were determined by ELISA. Lipoprotein profile, circulating and tissue lipids, and vascular pro-inflammatory mediators were determined using standardized methods while atherosclerosis was determined by confocal microscopy studies and non-invasive imaging (PET/CT and Doppler ultrasonography). Studies treating human macrophages (hMΦ) and coronary vascular smooth muscle cells (hcVSMC) with rabbit serums were performed to ascertain the potential impact of anti-P3 Abs on the functionality of these crucial cells.
Results: P3 immunization specifically induced the production of anti-P3 antibodies (Abs) and did not alter the lipoprotein profile. HFD strongly induced cholesteryl ester (CE) accumulation in the aorta of both the control and IrP groups, and their serum dose-dependently raised the intracellular CE of hMΦ and hcVSMC, promoting TNFR1 and phospho-NF-kB (p65) overexpression. These HFD pro-inflammatory effects were dramatically decreased in the aorta of P3-immunized rabbits and in hMΦ and hcVSMC exposed to the P3 rabbit serums. Microscopy studies revealed that P3 immunization reduced the percentage of lipids, macrophages, and SMCs in the arterial intima, as well as the atherosclerotic extent and lesion area in the aorta. PET/CT and Doppler ultrasonography studies showed that the average standardized uptake value (SUVmean) of the aorta and the arterial resistance index (ARI) of the carotids were more upregulated by HFD in the control and IrP groups than the P3 group.
Conclusions: P3 immunization counteracts HFD-induced fatty streak formation in rabbits. The specific blockade of the LRP1 (CR9) domain with Anti-P3 Abs dramatically reduces HFD-induced intracellular CE loading and harmful coupling to pro-inflammatory signaling in the vasculature.
2020-09-16T06:56:56Z
2020-09-16T06:56:56Z
2020-02-10
artículo
Theranostics 10(7): 3263-3280 (2020)
1838-7640
http://hdl.handle.net/10261/219666
10.7150/Thno.37305
http://dx.doi.org/10.13039/501100002809
http://dx.doi.org/10.13039/501100004587
http://dx.doi.org/10.13039/501100003329
http://dx.doi.org/10.13039/100008666
32194867
eng
Publisher's version
https://doi.org/10.7150/thno.37305
Sí
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/IJCI-2016-29393
https://creativecommons.org/licenses/by/4.0/
openAccess
Ivyspring International Publisher