P743Hypercholesterolemia leads to hyperactivation of mononuclear cells by increased intracellular signaling and as a result of enhanced chemokinesis

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Abstract

Purpose: Monocytes contribute to both vacular repair as well as atherogenesis. This contribution is dependent on monocyte function. Hypercholesterolemia (HC) is a cardiovascular risk factor affecting monocyte function and resulting in reduced chemotactic response towards chemokines such as VEGFA ("VEGF resistance") or MCP-1. The aim of the current project is to investigate the molecular mechanisms underlying HC-related monocyte dysfunction resulting in VEGF resistance.

Methods: We have established an in vitro model of HC by exposing primary human monocytes or mononuclear THP-1 cells to various lipid fractions to simulate the in vivo situation. Using this system, we characterized the effects of native low denisity lipoprotein (nLDL) and oxidized LDL (oxLDL) on mononuclear cell function and investigated the underlying molecular mechanisms.

Results: Our results show that exposure of monocytes to either nLDL or oxLDL inhibited MCP-1-induced chemotaxis, while both nLDL and oxLDL enhanced the baseline migration (chemokinesis). Interestingly, the effects of oxLDL on mononuclear cell migration are stronger than those of nLDL. OxLDL enhanced chemokinesis up to 50% compared to the control, whereas nLDL just showed the tendency to enhance basal mononuclear cell chemokinesis. Likewise, nLDL and oxLDL enhanced adhesion of THP-1 cells on endothelial cells in a concentration dependent manner. In addition, both LDL fractions activated signaling pathways like ERK and p38, and induced the expression of downstream target molecules.

Conclusions: These results indicate that HC leads to hyperactivation of mononuclear cells by enhancement of downstream signaling cascades thereby increaseing chemokinesis and adhesion on endothelial cells. This activation of signalling pathway activation makes monocytes refractory for further ligand induced chemotaxis. Increases in basal mononuclear cell chemokinesis and adhesion could explain increased monocyte infiltration into the vessel wall as observed during plaque progression during atherogenesis.

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