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Theranostics 2020; 10(7):3263-3280. doi:10.7150/thno.37305 This issue Cite

Research Paper

Immunization with the Gly1127-Cys1140 amino acid sequence of the LRP1 receptor reduces atherosclerosis in rabbits. Molecular, immunohistochemical and nuclear imaging studies

Olga Bornachea1,2, Aleyda Benitez-Amaro1,2, Angela Vea1, Laura Nasarre1, David de Gonzalo-Calvo1,2,3, Juan Carlos Escola-Gil4, Lidia Cedo4, Antoni Iborra5, Laura Martínez-Martínez6, Candido Juarez6, Juan Antonio Camara7, Carina Espinet8, Maria Borrell-Pages3,9, Lina Badimon3,9,10, Joan Castell8, Vicenta Llorente-Cortés1,2,3✉

1. Institute of Biomedical Research of Barcelona (IIBB). Spanish National Research Council (CSIC), Barcelona, Spain.
2. Lipids and Cardiovascular Pathology. Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau. Barcelona. Spain.
3. CIBER enfermedades cardiovasculares (CIBERcv).
4. Metabolic Basis of Cardiovascular Risk, Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau. CIBER de Diabetes y enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona. Spain.
5. SCAC, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain
6. Department of Immunology, Institut de Recerca and Hospital Santa Creu i Sant Pau, Barcelona, Spain.
7. Preclinical Imaging Platform. Vall dHebron Institute of Research. Barcelona, Spain.
8. Department of Nuclear Medicine, Institut de Diagnòstic per la Imatge (IDI), Hospital General Universitari Vall d'Hebrón, Universitat Autònoma de Barcelona, Barcelona, Spain.
9. Cardiovascular Program ICCC, Institut de Recerca Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
10. Cardiovascular Research Chair, UAB, Barcelona, Spain

✉ Corresponding author: Vicenta Llorente-Cortés, Lipids and Cardiovascular Pathology group leader, IIBB-CSIC,IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Sant Antoni Mª Claret, 167, 08025 Barcelona. Phone: +34 935565888, Fax: +34 9355 More

Citation:
Bornachea O, Benitez-Amaro A, Vea A, Nasarre L, de Gonzalo-Calvo D, Escola-Gil JC, Cedo L, Iborra A, Martínez-Martínez L, Juarez C, Camara JA, Espinet C, Borrell-Pages M, Badimon L, Castell J, Llorente-Cortés V. Immunization with the Gly1127-Cys1140 amino acid sequence of the LRP1 receptor reduces atherosclerosis in rabbits. Molecular, immunohistochemical and nuclear imaging studies. Theranostics 2020; 10(7):3263-3280. doi:10.7150/thno.37305. https://www.thno.org/v10p3263.htm
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Abstract

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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.

Keywords: LRP1 (CR9), atherosclerosis, LDL, vascular cholesteryl esters, NF-kB, TNFR1, 18F-FDG-PET/CT, Doppler ultrasonography, inflammation

Citation styles

APA
Bornachea, O., Benitez-Amaro, A., Vea, A., Nasarre, L., de Gonzalo-Calvo, D., Escola-Gil, J.C., Cedo, L., Iborra, A., Martínez-Martínez, L., Juarez, C., Camara, J.A., Espinet, C., Borrell-Pages, M., Badimon, L., Castell, J., Llorente-Cortés, V. (2020). Immunization with the Gly1127-Cys1140 amino acid sequence of the LRP1 receptor reduces atherosclerosis in rabbits. Molecular, immunohistochemical and nuclear imaging studies. Theranostics, 10(7), 3263-3280. https://doi.org/10.7150/thno.37305.

ACS
Bornachea, O.; Benitez-Amaro, A.; Vea, A.; Nasarre, L.; de Gonzalo-Calvo, D.; Escola-Gil, J.C.; Cedo, L.; Iborra, A.; Martínez-Martínez, L.; Juarez, C.; Camara, J.A.; Espinet, C.; Borrell-Pages, M.; Badimon, L.; Castell, J.; Llorente-Cortés, V. Immunization with the Gly1127-Cys1140 amino acid sequence of the LRP1 receptor reduces atherosclerosis in rabbits. Molecular, immunohistochemical and nuclear imaging studies. Theranostics 2020, 10 (7), 3263-3280. DOI: 10.7150/thno.37305.

NLM
Bornachea O, Benitez-Amaro A, Vea A, Nasarre L, de Gonzalo-Calvo D, Escola-Gil JC, Cedo L, Iborra A, Martínez-Martínez L, Juarez C, Camara JA, Espinet C, Borrell-Pages M, Badimon L, Castell J, Llorente-Cortés V. Immunization with the Gly1127-Cys1140 amino acid sequence of the LRP1 receptor reduces atherosclerosis in rabbits. Molecular, immunohistochemical and nuclear imaging studies. Theranostics 2020; 10(7):3263-3280. doi:10.7150/thno.37305. https://www.thno.org/v10p3263.htm

CSE
Bornachea O, Benitez-Amaro A, Vea A, Nasarre L, de Gonzalo-Calvo D, Escola-Gil JC, Cedo L, Iborra A, Martínez-Martínez L, Juarez C, Camara JA, Espinet C, Borrell-Pages M, Badimon L, Castell J, Llorente-Cortés V. 2020. Immunization with the Gly1127-Cys1140 amino acid sequence of the LRP1 receptor reduces atherosclerosis in rabbits. Molecular, immunohistochemical and nuclear imaging studies. Theranostics. 10(7):3263-3280.

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