LRP1 derived peptides as a therapeutic strategy in atherosclerosis. Biochemical, in vitro and in vivo studies

• Abstract
• Webcast

Abstract

Background and Aims

agLDL uptake by LRP1 favors the formation of foam cells from SMC, a key process in atherosclerosis. The Cluster II of the LRP1 receptor, and in particular the C-terminal half of domain CR9, comprising the region Gly¹¹²⁷-Cys¹¹⁴⁰ (P3 peptide), is critical for interaction with agLDL. The P3 peptide, and its stabilized versions, the DP3 retro-enantiomer, inhibits the process of aggregation of LDL by 80-90% in standardized biochemical assays. The objective of this work was to study the effect of DP3 peptide on the formation of foam cells and atherosclerosis in an in vitro and in vivo model, respectively.

Methods

The effectiveness of the DP3 peptide in inhibiting foam cell formation from hcVSMC was analyzed by chromatographic analysis of intracellular lipids and confocal microscopy. The impact of treatment with DP3 in vivo was studied in knockout mice for LDLR to which the peptide was injected subcutaneously during 21 days. Plasma lipid levels were analyzed in an autoanalyzer. The atherosclerosis load in the aortic arch was immunohistochemically.

Results

In the presence of DP3, LDL was not aggregated and did not increase the intracellular accumulation of cholesterol in hcVSMC above physiological levels. These results were confirmed by confocal microscopy experiments. Optical microscopy showed that treatment with the peptide did not alter the viability of the cells. In the murine model, DP3 significantly reduced atherosclerosis induced by a high cholesterol diet.

Conclusions

Peptides derived from LRP1 emerge as potentially useful tools in the treatment of atherosclerosis, particularly in people with LDL prone to aggregation.

Hide

Webcast

[session]

[presentation]

[presenter]

Hide