Myeloperoxidase (MPO) belongs to the heme peroxidase family, which includes a set of enzymes with potent oxidoreductase activity. MPO is considered an important part of the innate immune system's microbicidal arm and is secreted by neutrophils and macrophages. Interestingly, this enzyme has been implicated in the pathogenesis of several diseases including atherosclerosis. MPO is ubiquitous in atherosclerotic lesions and contributes to the initiation and progression of the disease primarily by oxidizing low‑density lipoprotein (LDL) particles. MPO is the only human enzyme with the ability to produce hypochlorous acid (HOCl) at physiological chloride concentrations and HOCl‑LDL epitopes were shown to be present inside atheromatous lesions making it a physiologically relevant model for the oxidation of LDL. It has been shown that MPO modified LDL is not able to bind to the native LDL receptor and is recognized instead by scavenger receptors on both endothelial cells and macrophages, which can lead to endothelial dysfunction and foam cell formation, respectively; both of which are instrumental in the progression of the disease. Meanwhile, several studies have proposed MPO as a biomarker for cardiovascular diseases where high levels of this enzyme were linked to an increased risk of developing coronary artery disease. Overall, there is sufficient evidence supporting the value of MPO as a crucial player in health and disease. Thus, future research should be directed towards investigating the still unknown processes associated with this enzyme. This may assist in better understanding the pathophysiological role of MPO, as well in the development of therapeutic strategies for protecting against the deleterious effects of MPO in numerous pathologies such as atherosclerosis.

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.

Radiation-induced cardiac toxicity is a recognized complication in patients undergoing thoracic radiotherapy. A crucial manifestation of this toxicity is the damage caused to coronary arteries, which can result in accelerated atherosclerosis that may remain undetected for many years. As cancer survival rates continue to improve, the incidence of radiation-induced coronary artery disease (RICAD) is increasing, making it one of the leading causes of morbidity and mortality among patients treated with radiotherapy for mediastinal cancers. The pathophysiology of RICAD involves a complex interplay of cellular mechanisms, including endothelial dysfunction, inflammation, and fibrosis. These processes are related to several molecular insults such as DNA damage, telomere erosion, and mitochondrial dysfunction. However, to fully understand the initiation and progression of the disease, further research is critical to uncover additional contributing factors. Different strategies for preventing cardiovascular complications in cancer patients are gaining significant attention. Recent advancements in radiotherapy, particularly the new FLASH radiotherapy technique, show promise in reducing the incidence of these complications. This review focuses on the effects of radiotherapy on coronary artery disease, exploring the underlying cellular and molecular mechanisms, as well as potential strategies to prevent RICAD.

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.

Cellular senescence is a state of permanent cell cycle arrest accompanied by metabolic activity and characteristic phenotypic changes. This process is crucial for developing age-related diseases, where excessive calorie intake accelerates metabolic dysfunction and aging. Overnutrition disturbs key metabolic pathways, including insulin/insulin-like growth factor signaling (IIS), the mammalian target of rapamycin (mTOR), and AMP-activated protein kinase. The dysregulation of these pathways contributes to insulin resistance, impaired autophagy, exacerbated oxidative stress, and mitochondrial dysfunction, further enhancing cellular senescence and systemic metabolic derangements. On the other hand, dysfunctional endothelial cells and adipocytes contribute to systemic inflammation, reduced nitric oxide production, and altered lipid metabolism. Numerous factors, including extracellular vesicles, mediate pathological communication between the vascular system and adipose tissue, amplifying metabolic imbalances. Meanwhile, caloric restriction (CR) emerges as a potent intervention to counteract overnutrition effects, improve mitochondrial function, reduce oxidative stress, and restore metabolic balance. CR modulates pathways such as IIS, mTOR, and sirtuins, enhancing glucose and lipid metabolism, reducing inflammation, and promoting autophagy. CR can extend the health span and mitigate age-related diseases by delaying cellular senescence and improving healthy endothelial–adipocyte interactions. This review highlights the crosstalk between endothelial cells and adipocytes, emphasizing CR potential in counteracting overnutrition-induced senescence and restoring vascular homeostasis.

Cardiovascular disease associated with 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 lipoproteins (LDL). Early observations have associated fibrin deposition with atheroma plaque formation, which has led to the proposition that a decrease in endothelial cell fibrinolysis may negatively influence atherogenesis. It has been recently demonstrated that myeloperoxidase modified LDL (MoxLDL) decreases endothelial cell profibrinolytic capacity in real-time. The present study investigated the role of MoxLDL in endothelial cell dysfunction by determining the molecules that may be involved in decreasing the fibrinolysis of human aortic endothelial cells (HAEC). Accordingly, reverse transcription-quantitative PCR was performed to screen for the differential expression of major genes that are implicated in the fibrinolytic process. In addition, the response of the latter cell type to MoxLDL was compared with bovine aortic endothelial (BAE) cells. Furthermore, the effect of the treatment on the generation of reactive oxygen species (ROS) was also determined. Although the current study did not demonstrate an association between MoxLDL treatment and a change in the expression of any major fibrinolytic factor in HAEC, a discrepancy between HAEC and BAE cells with respect to their response to modified LDL treatment was observed. The result have also demonstrated that MoxLDL does not increase ROS generation in HAEC as opposed to the other major type of modified LDL, cupper oxidized LDL (CuoxLDL) that was reported to exhibit a positive effect at this level. The present study provided important insight into the different effects of MoxLDL and CuoxLDL in endothelial cells, which may aid future studies to determine the various signaling pathways that are promoted by these molecules. The results of the present study may be utilized to identify potential molecular drug targets for the treatment of atherosclerosis.