Myeloperoxidase-Oxidized LDL Activates Human Aortic Endothelial Cells through the LOX-1 Scavenger Receptor.

Layal El-Hajjar,Rana Andraos,Marwan El-Sabban,Jalil Daher,Judy Hindieh

doi:10.3390/ijms23052837

Abstract

Cardiovascular disease as a result of atherosclerosis is a leading cause of death worldwide. Atherosclerosis is primarily caused by the dysfunction of vascular endothelial cells and the subendothelial accumulation of oxidized forms of low-density lipoprotein (LDL). Early observations have linked oxidized LDL effects in atherogenesis to the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) scavenger receptor. It was shown that LOX-1 is upregulated by many inflammatory mediators and proatherogenic stimuli including cytokines, reactive oxygen species (ROS), hemodynamic blood flow, high blood sugar levels and, most importantly, modified forms of LDL. Oxidized LDL signaling pathways in atherosclerosis were first explored using LDL that is oxidized by copper (Cuox-LDL). In our study, we used a more physiologically relevant model of LDL oxidation and showed, for the first time, that myeloperoxidase oxidized LDL (Mox-LDL) may affect human aortic endothelial cell (HAEC) function through the LOX-1 scavenger receptor. We report that Mox-LDL increases the expression of its own LOX-1 receptor in HAECs, enhancing inflammation and simultaneously decreasing tubulogenesis in the cells. We hypothesize that Mox-LDL drives endothelial dysfunction (ED) through LOX-1 which provides an initial hint to the pathways that are initiated by Mox-LDL during ED and the progression of atherosclerosis.

Highlights

Atherosclerosis is a clinical condition for which multiple genetic and environmental causal factors have been proposed
We investigated, for the first time, the interaction between Mox-low-density lipoprotein (LDL) and lipoprotein receptor-1 (LOX-1) in endothelial cells
Our data indicate that myeloperoxidase oxidized LDL (Mox-LDL) may affect human aortic endothelial cell (HAEC) function through the LOX-1 scavenger receptor

Summary

Introduction

Atherosclerosis is a clinical condition for which multiple genetic and environmental causal factors have been proposed. Other studies have shown a correlation between myeloperoxidase oxidized LDL (Mox-LDL) and different levels of endothelial cell dysfunction (ED) [7]. It is already known that dysfunctional endothelial cells have reduced motility, which could affect their ability to undergo angiogenesis, an essential physiological mechanism seen in health and diseases including atherosclerosis [9–12]. As far as Mox-LDL is concerned, we had previously reported [18,19] that Mox-LDL induces ED by reducing both the fibrinolytic capacity of endothelial cells as well as their ability to migrate and undergo wound healing in vitro. Our previous results suggested that high Mox-LDL levels in patients would impair the potential of endothelial cells to cope with the damaged endothelium, negatively contributing to the progression of the atheroma plaque. Despite the significance of the finding, we did not link this observation to any signaling transduction pathway, including the receptor that can bind to Mox-LDL and mediate its effects in the cell

Objectives

Methods

Results

Conclusion