LRP1-based immunotherapy would reduce remodeling of the cardiac extracellular matrix due to cholesterol accumulation

A study coordinated by Dr. Vicenta Llorente-Cortés, a researcher at CIBERCV in the Research Institute of the Hospital de la Santa Creu i Sant Pau – IIB Sant Pau and the Biomedical Research Institute of Barcelona (IIBB-CSIC), reveals that LRP1-based immunotherapy reduces cardiac extracellular matrix (ECM) remodeling induced by intracellular accumulation of esterified cholesterol in cardiomyocytes. The research, which involved collaboration from CIBERDEM, UB, the CIRIMAT Institute in Toulouse (France), and the University of Córdoba (Argentina), has been published in the Journal of Medicinal Chemistry.

The study analyzed the effect of anti-P3 antibodies on the biological alterations of cardiac ECM induced by a cholesterol-enriched diet. The study demonstrates that immunizing rabbits with the P3 sequence of the LRP1 receptor produces specific anti-P3 antibodies in the blood that selectively and specifically block the entry of esterified cholesterol transported by lipoproteins into cardiomyocytes.

The results show that a cholesterol-rich diet increases intracellular levels of esterified cholesterol and triglycerides in cardiomyocytes, the extracellular level of collagen, the degree of fibrosis, water retention, and plasticization of the ECM in the heart. It is noteworthy that in immunized animals, anti-P3 antibodies specifically reduce intracellular accumulation of esterified cholesterol within cardiomyocytes, and this effect is sufficient to reduce collagen accumulation, water retention in the ECM, and cardiac fibrosis.

These findings demonstrate that anti-P3 antibodies improve cardiac extracellular matrix remodeling by reducing the accumulation of intracellular esterified cholesterol in cardiomyocytes.

This study, along with others published by the same group on this LRP1-based immunotherapy model (Actis-Dato V et al. Biomed Pharmacother. 2022), provides a solid foundation for the development of immune-based therapies focused on reducing esterified cholesterol accumulation in the heart as a potentially useful therapeutic strategy in the management of heart failure.

Reference article: Samouillan V, Garcia E, Benitez-Amaro A, La Chica Lhoëst MT, Dandurand J, Actis Dato V, Guerra JM, Escolà-Gil JC, Chiabrando G, Enrich C, Llorente-Cortes V. Inhibitory Effects of LRP1-Based Immunotherapy on Cardiac Extracellular Matrix Biophysical Alterations Induced by Hypercholesterolemia. J Med Chem. 2023 May 11;66(9):6251-6262. doi: 10.1021/acs.jmedchem.2c02103. Epub 2023 Apr 28. PMID: 37116069; PMCID: PMC10184115.