Inhibitory Effects of LRP1-Based Immunotherapy on Cardiac Extracellular Matrix Biophysical Alterations Induced by Hypercholesterolemia

• Published in: Journal of medicinal chemistry Vol. 66; no. 9; pp. 6251 - 6262
• Main Authors: Samouillan, Valerie, Garcia, Eduardo, Benitez-Amaro, Aleyda, La Chica Lhoëst, Maria Teresa, Dandurand, Jany, Actis Dato, Virginia, Guerra, Jose Maria, Escolà-Gil, Joan Carles, Chiabrando, Gustavo, Enrich, Carlos, Llorente-Cortes, Vicenta
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 11-05-2023
• Subjects: Animals; Cardiology and cardiovascular system; Cholesterol Esters - metabolism; Collagen; Diet, High-Fat; Extracellular Matrix - metabolism; Fibrosis; Human health and pathology; Hypercholesterolemia - metabolism; Hypercholesterolemia - therapy; Immunology; Immunotherapy; Life Sciences; Rabbits
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c02103

The accumulation of lipids in cardiomyocytes contributes to cardiac dysfunction. The specific blockage of cardiomyocyte cholesteryl ester (CE) loading by antibodies (Abs) against the P3 sequence (Gly1127–Cys1140) of the LRP1 receptor improves cardiac insulin sensitivity. The impact of anti-P3 Abs on high-fat diet (HFD)-induced cardiac extracellular matrix (ECM) biophysical alterations was analyzed. Both IrP (without Abs) and P3-immunized rabbits (with Abs) were randomized into groups fed either HFD or a standard chow diet. Cardiac lipids, proteins, and carbohydrates were characterized by Fourier transform infrared spectroscopy in the attenuated total reflectance mode. The hydric organization and physical structure were determined by differential scanning calorimetry. HFD increased the levels of esterified lipids, collagen, and α-helical structures and upregulated fibrosis, bound water, and ECM plasticization in the heart. The inhibitory effect of anti-P3 Abs on cardiac CE accumulation was sufficient to reduce the collagen-filled extracellular space, the level of fibrosis, and the amount of bound water but did not counteract ECM plasticization in the heart of hypercholesterolemic rabbits.