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

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.

Role of myeloperoxidase in inflammation and atherosclerosis (Review)

“…However, despite recent advancements in the field and the increase in our understanding of the effects of Mox-LDL in the development of atherosclerosis, there remain several knowledge gaps pertaining to the mechanisms regulating the role of Mox-LDL in macrophage and EC pathobiology during the progression of the disease. In the latter model, as already mentioned, our recent results provide an updated knowledge on the signaling pathways that are promoted by Mox-LDL by providing initial insights into its corresponding scavenger receptor LOX-1( 69 ). In light of the latter finding, conceiving anti-atherogenic strategies that target the Mox-LDL-LOX-1 signaling axis as a therapeutic target may be extremely valuable in the context of treating atherosclerotic diseases and alleviating its symptoms.…”

“…Meanwhile, our research group has reported for the first time that the LOX-1 scavenger receptor might regulate the inflammatory response of HAECs to physiological levels of Mox-LDL. It was discovered that Mox-LDL upregulates the expression of its own receptor in HAECs and induces inflammation in the cells via LOX-1 in concert with the induction of this receptor ( 69 ). These observations may have important implications with regard to Mox-LDL-driven ED and provide an initial hint to the pathways that are initiated by Mox-LDL during ED and the progression of the atherosclerotic disease ( Fig.…”

Sea Buckthorn Polysaccharide Ameliorates Colitis

“…Chemokines CCL2 and CCL5 have important functions in attracting and stimulating macrophages during inflammation and are implicated in the development of various inflammatory conditions [61][62][63]. Increased MPO activity and levels of MPO-derived oxidative products are associated with various inflammatory diseases [64,65]. SBP also has been shown to decrease the levels of MPO, thereby potentially mitigating the enzyme's excessive activity linked to inflammation.…”

Identification of cuproptosis-related biomarkers in aortic dissection：new insights from bioinformatic analysis

“…48,49 Copper participates in ROS formation and oxidative modi cations of LDL cholesterol, thereby promoting atherosclerotic plaque formation. 50 Further research is necessary to fully elucidate the exact mechanisms underlying this relationship. Nevertheless, this knowledge presents potential avenues for therapeutic interventions aimed at reducing LDL cholesterol levels and mitigating the risk of aortic dissection in susceptible individuals.…”