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Changes in macrophages and endothelial cells mechanics treated with native LDL from donors with CVD

ABSTRACT: Atherosclerosis is a progressive and multifactorial vascular disorder characterized by lipid accumulation, chronic inflammation, and structural alterations in the arterial wall. This condition disrupts normal endothelial function, including the biomechanical properties of endothelial cells, which play a crucial role in maintaining vascular homeostasis. Mechanical dysfunction in these cells contributes to increased vascular permeability and topographical irregularities that disturb hemodynamic flow, fostering an environment conducive to plaque development. A growing body of evidence suggests that low-density lipoprotein (LDL) exacerbates these dysfunctions by increasing cellular stiffness. As endothelial cells act as primary mechanosensors within blood vessels, their altered mechanical state is a critical factor in early atherogenesis. In this study, we explored the molecular pathways by which native LDL, derived from individuals with cardiovascular disease, affects the mechanical and structural properties of endothelial cells and macrophages. Our analyses revealed that exposure to native LDL triggers a pronounced reorganization of the actin cytoskeleton, primarily mediated through Rho GTPase signaling, along with notable augmentation of the tubulin network. These cytoskeletal changes were accompanied by compromised cell adhesion, weakened intercellular connectivity, and impaired extracellular matrix integrity—all of which are pivotal to endothelial barrier function. Furthermore, gene expression profiling indicated a significant upregulation of LOX, HMOX1, RND1, RUNX1, and TFRC in LDL-treated endothelial cells, suggesting a disruption in iron metabolism. This dysregulation likely contributes to oxidative stress through reactive oxygen species (ROS) production, thereby accelerating atherosclerotic plaque formation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303475 | GEO | 2025/07/30

REPOSITORIES: GEO

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Project description:LRP1 and, in particular the region that spans the C-terminal half of domain CR9 (from Gly1127 to Cys1140), named LP3, is essential for aggregated LDL internalization and human coronary vascular smooth muscle cells (hcVSMC)-cholesterol loading. Here, we investigated whether LP3 and its retro-enantio version (DP3) are protective against sphingomyelinase (SMase) and phospholipase 2 (PLA2)-induced LDL aggregation, the structural basis underlying this protection and the impact that LRP1-derived peptides might have on hcVSMC-cholesterol loading and cholesterol-modulated signaling pathways. For this purpose, biochemical, biophysical, molecular, proteomic, and cellular experiments were performed. Turbidimetry measurements show that LP3 and DP3 inhibit LDL aggregation induced by SMase and PLA2 in a dose-dependent manner, although the efficacy of DP3 is higher. Gel filtration chromatography (GFC) and transmission electron microscopy (TEM) show that LP3, and more efficiently DP3, almost completely counteract the increased percentage of aggregated LDL induced by both SMase and PLA2, respectively. Native polyacrilamide gradient gel electrophoresis (GGE), agarose gel electrophoresis (AGE) and high-performance thin layer chromatography (HPTLC) partitioning of LDL phospholipids indicated that LP3 and DP3 prevent SMase-induced alterations in LDL size, electric charge and phospholipid content but not those induced by PLA2. In contrast, LP3 and DP3 show high efficacy to counteract changes in ApoB-100 conformation induced by both SMase and PLA2. Together, these results indicate that LRP1-derived peptides protect LDL against aggregation induced by SMase and PLA2 through a common mechanism based on their capacity to prevent ApoB-100 conformational changes. Proteomics and computational modeling methods suggest that LRP1 derived peptides are able to establish strong electrostatic interactions with a specific ApoB-100 basic region. TLC and confocal microscopy show that DP3 with higher efficacy than LP3 significantly reduce intracellular cholesteryl ester accumulation induced by SMase-LDL in hcVSMC. Moreover, proteomics studies evidence several signaling pathways modulated by SMase-LDL that are counteracted specifically by DP3. These findings demonstrate that LRP1 derivative peptides protect against LDL aggregation and preserve vascular cells against cholesterol loading and associated alterations in critical signal pathways

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Changes in macrophages and endothelial cells mechanics treated with native LDL from donors with CVD

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