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Atherosclerosis is a chronic inflammatory disease that involves modified low-density lipoproteins (LDL) which play a pivotal role in the initiation and progression of the disease. Myeloperoxidase oxidized LDL (Mox-LDL) is considered to be the most patho-physiologically relevant type of modified LDL and has been reported to be ubiquitously present in atheroma plaques of patients with atherosclerosis. Besides its involvement in the latter disease state, Mox-LDL has also been shown to be implicated in the pathogenesis of various illnesses including sleep disorders, which are in turn associated with heart disease and depression in many intricate ways. Meanwhile, we have recently shown that lox-1-mediated Mox-LDL signaling modulates neuroserpin activity in endothelial cells, which could have major implications that go beyond the pathophysiology of stroke and cerebrovascular disease (CD). Of note is that tissue plasminogen activator (tPA), which is the main target of neuroserpin in the brain, has a crucial function in the processing of brain-derived neurotrophic factor (BDNF) into its mature form. This factor is known to be involved in major depressive disorder (MDD) development and pathogenesis. Since tPA is more conventionally recognized as being involved in fibrinolytic mechanisms, and its effect on the BDNF system in the context of MDD is still not extensively studied, we speculate that any Mox-LDL-driven change in the activity of tPA in patients with atherosclerosis may lead to a decrease in the production of mature BDNF, resulting in impaired neural plasticity and depression. Deciphering the mechanisms of interaction between those factors could help in better understanding the potentially overlapping pathological mechanisms that regulate disease processes in CD and MDD, supporting the possibility of novel and common therapeutic opportunities for millions of patients worldwide.

Cardiovascular diseases (CVDs) linked to atherosclerosis remains the leading cause of death worldwide. Atherosclerosis is primarily caused by the accumulation of oxidized forms of low density lipoprotein (LDL) in macrophages (MΦs) in the subendothelial layer of arteries leading to foam cell and fatty streak formation. Many studies suggest that LDL that is modified by myeloperoxidase (MPO) is a key player in the development of atherosclerosis. MΦs can adopt a variety of functional phenotypes that include mainly the proinflammatory M1 and the anti-inflammatory M2 MΦ phenotypes which are both implicated in the process of atherogenesis. In fact, MΦs that reside in atherosclerostic lesions were shown to express a variety of phenotypes ranging between the M1- and M2 MΦ types. Recently, we pointed out the involvement of MPO oxidized-LDL (Mox-LDL) in increasing inflammation in MΦs by reducing their secretion of IL-10. Since little is known about Mox-LDL-mediated pro-atherosclerostic responses in MΦs, our study aimed at analyzing the in vitro effects of Mox-LDL at this level through making use of the well-established model of human THP-1-derived Mφs. Our results demonstrate that Mox-LDL has no effect on apoptosis, reactive oxygen species (ROS) generation and cell death in our cell model; yet, interestingly, our results show that Mox-LDL is significantly engulfed at a higher rate in the different MΦ subtypes supporting its key role in foam cell formation during the progression of the disease as well as previous data that were generated using another primary MΦ cell model of atherosclerosis., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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.

Macrophages (Mφs) play a crucial role in the development of atherosclerosis by engulfing modified LDL particles and forming foam cells, the hallmark of atherosclerosis. Many studies suggest that myeloperoxidase-oxidized LDL (Mox-LDL) is an important pathophysiological model for LDL modification in vivo . Classically (M1) and alternatively activated (M2) Mφs are both implicated in the process of atherogenesis. Mφs are highly plastic cells whereby they undergo repolarization from M1 to M2 and vice versa . Since little is known about the effects of Mox-LDL on Mφ polarization and repolarization, our study aimed at evaluating the in vitro effects of Mox-LDL at this level through making use of the well-established model of human THP-1-derived Mφs. Resting M0-Mφs were polarized toward M1- and M2-Mφs, then M0-, M1- and M2-Mφs were all treated with physiological concentrations of Mox-LDL to assess the effect of Mox-LDL treatment on Mφ polarization and repolarization. Treatment of M0-Mφs with a physiological concentration of Mox-LDL had no significant effects at the level of their polarization. However, treatment of M1-Mφs with Mox-LDL resulted in a significant reduction in their IL-10 cytokine secretion. Our results point to a potential role of Mox-LDL in increasing the pro-inflammatory state in Mφs through reducing the release of the anti-inflammatory cytokine, IL-10.