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.
Myeloperoxidase (MPO) belongs to the peroxidase-cyclooxygenase subgroup of the heme peroxidase family of enzymes. It is secreted by neutrophils and monocytes where it plays a crucial role in innate immunity (
Heme peroxidases are a ubiquitous group of enzymes with robust oxidoreductase activity. They contain a heme group, which acts as a redox cofactor for catalyzing the hydrogen peroxide (H2O2) mediated one- and two-electron oxidation reactions of numerous organic and inorganic molecules. One-electron donors such as organic molecules (AH2) are oxidized into their corresponding radicals (AH) and H2O2 is reduced to water (Reaction 1) (
MPO is one of the most prominent enzymes of the peroxidase-cyclooxygenase subgroup and is encoded by a gene located on the long arm of chromosome 17 (17q) with a size of 14 kb (
MPO is a crucial mediator of the intracellular microbicidal system of phagocytes and the host innate immune system. After synthesis, MPO is stored in the azurophilic granules of resting neutrophils and it is inactivated through inactivated when it is captured by anionic proteoglycans accompanied by the low pH milieu (
MPO has been implicated to varying extents in the pathogenesis of several diseases (
MPO is pervasive inside atherosclerotic lesions. MPO has been extensively shown to be present inside human atherosclerotic tissues (
Numerous studies including
High-density lipoprotein is renowned for its athero-protective characteristics including its antioxidant, anti-inflammatory, and antithrombotic properties. A reputed contribution of MPO to atherosclerosis involves targeting and modifying apolipoprotein A-I (apoA-I) of HDL resulting in the attenuation of the athero-protective role of HDL. MPO binds to helix 8 on apoA-I, and converts HDL into a dysfunctional form (
There is ample evidence showing that MPO and its downstream oxidative products cause ED. First, several peroxidases such as MPO act as a catalytic sink for NO, since NO is a substrate for the one-electron reactions of the peroxidases (
Several studies have established a relationship between varying levels of MPO and CVD, independent of classical risk factors. For instance, elevated levels of functional MPO per ml of blood and per leukocyte were linked with the risk of coronary artery disease (CAD) (
Atherosclerosis is a progressive chronic inflammatory disorder characterized by the interplay of multiple risk factors. High plasma LDL cholesterol levels are one of the most well-established risk factors underlying the development of atherosclerosis and cardiovascular problems. Conversely, low plasma LDL levels are associated with low cardiovascular risk. Indeed, individuals with exceedingly low LDL levels generally do not develop clinically relevant atherosclerosis, irrespective of the presence of other risk factors (
There exist several mechanisms for the oxidative modification of LDL. Different cells, enzymes, and cations are involved in the oxidation of LDL.
The exact processes underlying the formation of oxLDL
The majority of studies on the effect of oxLDL on monocytes/macrophages have been performed using Cuox-LDL which is not a physiologically relevant model of oxLDL (
In summary, LDL modified by the MPO/H2O2/Cl- system or directly by HOCl appears to activate macrophages and induce a stronger reaction in them compared with other forms of oxLDL.
There is a general consensus among scholars regarding the role of ED in the initiation of atherosclerosis, and oxLDL has the ability to facilitate ED in various manners (
In summary, there is a substantial body of evidence suggesting that MPO is implicated in health and in disease. Physiologically, MPO plays a role in innate microbial defenses by catalyzing the formation of powerful reactive oxygen intermediates, which are potent antimicrobial tools against phagocytosed pathogens. Beyond the role of MPO in antimicrobial defenses, there exist other uncharted important physiological roles of MPO (
On that same note, the ubiquitous presence of MPO in atherosclerotic lesions along with the newly reported effects of MPO-modified LDL in this particular context supports the notion that LDL that is oxidized by MPO should now be considered as the more pathophysiological model for LDL oxidation and that future research involving oxLDL should now use this form of modified LDL as a preferred model to study atherosclerosis. 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(
Nevertheless, these results are still insufficient and thus, should pave the way for ongoing research to further elucidate additional signaling pathways and novel functions of Mox-LDL; this would ultimately direct scientists towards a more complete understanding of the complex paradigm of ED in atherosclerosis. Moreover, regarding the effect of Mox-LDL on macrophage biology, we recently showed that Mox-LDL might play a potential role in the repolarization of THP-1 macrophages by increasing their pro-inflammatory state through the downregulation of the major anti-inflammatory cytokine IL-10(
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CF drafted the manuscript. JD conceived the review topic, and wrote and edited the manuscript. Both authors have read and approved the final manuscript. Data authentication is not applicable.
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The authors declare that they have no competing interests.
The enzymatic activities of the peroxidase-cyclooxygenase subgroup including MPO. (A) Reactions that are catalyzed by the peroxidase-cyclooxygenase subgroup. (B) The latter group includes MPO, which, though halide oxidation (predominant physiological enzymatic activity) is responsible for the production of modified LDL and HDL particles through the generation of HOCl and the chlorination of tyrosine residues in the protein moieties of those particles. MPO, myeloperoxidase; LDL, low-density lipoproteins; HDL, high-density lipoproteins; HOCl, hypochlorous acid.
The effects of MPO modified LDL on endothelial cells and macrophage models of atherosclerosis. LDL that has been oxidized by MPO is able to induce ED which is primarily demonstrated by an increase in inflammation and a decrease in the physiological properties of ECs such as cell motility and wound healing. Similarly, Mox-LDL is responsible for the increase in oxidative stress and inflammation in macrophages through the upregulation of the generation of ROS and the downregulation of the major anti-inflammatory cytokine IL-10 in these cells. MPO, myeloperoxidase; LDL, low-density lipoproteins; ED, endothelial dysfunction; EC, endothelial cell; Mox-LDL, MPO oxidized LDL; ROS, reactive oxygen species; miR, microRNA; HO-1, heme oxygenase 1; LOX-1, lectin-like oxLDL receptor-1; NRF2, nuclear factor erythroid 2-related factor 2; Gclm, glutamate-cysteine ligase modifier subunit.
The primary effects of Mox-LDL during the evolution of atherosclerosis. Mox-LDL is responsible for the activation of ECs through the LOX-1 scavenger receptor. This leads to the recruitment of monocytes to the sub-endothelial layer where they differentiate into macrophages, engulfing modified LDL particles and leading to foam cell formation; at this point, Mox-LDL is capable of driving the polarization of those macrophages towards a more pro-inflammatory phenotype, which may play a major role in the progression of the disease. On the other hand, Mox-LDL can also decrease wound healing and fibrinolysis in ECs leading to more denudation in the endothelium and favoring the formation of blood clots, which will culminate in acute thrombotic events. LDL, low-density lipoproteins; Mox-LDL, myeloperoxidase oxidized LDL; EC, endothelial cell; LOX-1, lectin-like oxLDL receptor-1.
Studies assessing the role of myeloperoxidase in inflammation and disease.
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Heart failure | ( |