MPO FA and Its Role in a Variety of Pathologies

MPO FA and Its Role in a Variety of Pathologies

MPO FA is a potent oxidative enzyme and plays a role in a variety of pathologies. It mediates lipid peroxidation, protein nitration, and protein carbomylations.

In the presence of H2O2, MPO can also oxidize tyrosine to produce a tyrosyl radical. Tyrosyl radicals can oxidize protein Tyr residues to produce dityrosine crosslinks, which have been reported to enhance lipid peroxidation and atheroma formation.


MPO is an important oxidative stress and inflammation mediator that activates pro-inflammatory M1 microglial cells and N1 neutrophils in the ischemic brain. Treatment with 4-ABAH increased the proliferation and differentiation of astrocytes in the subventricular zone (SVZ), striatum, and cortex, and protected adult neurogenesis after stroke.

MPO catalyzes the formation of protein nitrotyrosine (NO2Tyr), a thiol-oxidant that is widely involved in inflammatory responses. NO2Tyr nitration is thought to occur through the action of PMN degranulation and MPO-catalyzed peroxidase catalysis, with fibronectin identified as a major target protein in this process.

Inhibition of MPO with heparin and the low-molecular weight heparin enoxaparin significantly inhibited NO2Tyr formation in both cultured endothelial cells and rat aortic vessel explants. In addition, NO2Tyr immunoreactivity was reduced after zymosan preincubation in the liver of MPO-/- mice (Figure 4a).

The ability of MPO to generate NO2Tyr is thought to be a key factor in its proinflammatory role in the vasculature. NO2Tyr is a highly reactive oxidant that readily reacts with and destroys cell membranes, collagen, and lipids in the presence of Cl- and H2O2 (34). Inhibition of NO2Tyr can be achieved through activation of enzymes that remove H2O2 in competition with NO2Tyr formation or through reduction of the NADPH oxidase complexes that produce O2-*.

As a result, heparin can inhibit the binding of MPO and NO2Tyr to vascular endothelial cells via the chondroitin sulfate-dependent interaction between MPO and the O2*- and H2O2-generating enzyme xanthine oxidase (XO) as shown in Figure 2d. Inhibition of XO binding also inhibited MPO-catalyzed NO2Tyr formation in a dose-dependent manner, with increasing concentrations of XO being ineffective at inhibiting MPO-catalyzed NO2Tyr and ATP generation.

Similarly, heparin and enoxaparin pretreatments inhibited MPO-catalyzed oxidative stress in human endothelial cells. Similarly, heparin pretreatment of rat aortic tissue explants inhibited NO2Tyr formation (Figure 6). Conclusion: These results suggest that NO2Tyr-catalyzed oxidative and tyrosine nitration reactions may be critical to pathophysiology in both vascular tissue and the central nervous system, where they are thought to be involved in inflammation, neuroinflammation, and oxidative damage following stroke. This suggests that MPO inhibitors have translational values as therapeutic candidates for improving the outcome of ischemic stroke therapy practically.


MPO is an essential component of innate immunity and releases a variety of strong oxidants, including hypochlorous acid (HOCl), which kill bacteria and other invading pathogens. However, excessive production of MPO-derived oxidants can contribute to the development of numerous chronic inflammatory diseases and pathologies, including atherosclerosis, neurodegenerative disease, lung disease, arthritis, cancer and kidney disease.

In the cytoplasm, MPO consists of two dimeric proteins containing a heavy and light chain (Fig. 1a). The heavy chain MPO FA is anchored to the membrane via a disulfide bond and contains a modified iron protoporphyrin IX derivative (FeIX), which is the active site. The light chain is anchored to the cell surface through a disulfide bond and has a number of glycosylation sites. The active site of the heavy MPO chain is positioned in a deep cleft between the heavy and light chains that restricts access of the iron atom to H2O2.

Compound II, the catalytic intermediate of MPO, is oxidized to the ferric state of MPO through a series of two reactions: (i) a one-electron reduction of the FeIX side-chain with a protonated histidine ligand; or (ii) a reaction of the ferric species with superoxide radical anion (O2*-). This process may lead to the formation of an additional intermediate, Compound III, which combines the ferric and oxygen forms of MPO (119).

As with most bacterial enzymes, MPO can acquire iron from host tissues by oxidatively reacting heme side-chains. This is accomplished through a series of steric interactions between the heme group and Met-243, which results in the withdrawal of electron density from the heme and an alteration of planarity. In addition, a sulfonium ion (covalent) linkage with the heme is also formed, which removes the redox properties of the heme and causes it to undergo a rapid, oxidative deoxidation to the sulfoxide species. This is thought to be a mechanism by which bacteria can overcome a host’s redox properties, and thereby deceive the host into actively internalizing a lethal oxidant, such as MPO.

In addition, Compound II can generate free tyrosyl radicals through oxidation of protein Tyr residues, which have been reported to crosslink with lipids in cells and in in vitro models, and can even initiate LDL lipid peroxidation in vitro. The formation of these tyrosyl radicals is also thought to contribute to apoptosis in MPO-dependent cells (99). In vivo, MPO appears extracellularly and can promote inflammation, as well as causing tissue damage.


An endothelial cell is a type of specialized cell that lines pathways in the body, such as blood vessels and lymphatic vessels. The cells have a diameter of about.1 to 10 micrometers, and they can grow to be over 1 trillion in number (Bauch and Caron, 2015).

These cells are important for your health because they help keep your blood vessels open so that blood can move freely throughout your body. They also respond to changes in temperature, stress levels and medications you take.

The endothelial cell is a major player in the development of many inflammatory diseases, including atherosclerosis, rheumatoid arthritis, cardiovascular disease, and cancer. Its production of hypochlorous acid (HOCl) is essential in the immune response, but it can also initiate oxidative damage, which leads to a variety of chronic diseases.

HOCl-mediated oxidative damage is dependent on the availability of NADPH oxidase, which produces the hydroxyl radical, or O2-*. O2-* can be regulated by the presence of NO*, which can inhibit HOCl formation by promoting S-nitrosylation of the key p47phox subunit of NADPH oxidase. Moreover, NO* can enhance the activity of peroxiredoxins and catalase in competition with MPO, limiting MPO-mediated oxidant production.

Besides the direct oxidant effects of MPO, it can induce lipid peroxidation and protein-bound nitrotyrosine via the formation of a tyrosyl radical that can also cross-link proteins and activate enzymes in the cell. This tyrosyl radical is thought to play a critical role in cellular signaling and tissue remodeling [118].

In the brain, MPO is increased following ischemia-reperfusion injury in both transient middle cerebral artery occlusion (tMCAO) and permanent MCAO models (Barone et al., 1995). In tMCAO, ischemic penumbra cells express higher MPO than the ischemic core at 6 h of ischemia onset and peak at day 5.

Several animal studies have shown that MPO FA is highly effective in mediating ischemia-reperfusion injury, as well as oxidative stress and neuroinflammation, in vivo. This is because MPO can produce a range of reactive species, such as HOCl and oxygen free radicals (O2f-), that are known to trigger oxidative tissue damage in several chronic diseases.


Adult neurogenesis produces newborn neurons from neural stem cells (NSCs) and neural progenitors in the adult neurogenic niche. This process is critical for brain development and plasticity. In addition, perturbation of neurogenesis contributes to several human diseases, including cognitive impairment and neurodegenerative disorders.

Previously, neuroanatomists believed that the nervous system was a fixed, inflexible and non-regenerative organ. However, in the second half of the 20th century, researchers discovered that neurons continue to form throughout adult life. During this time, scientists also discovered that neurogenesis takes place in different areas of the brain. These discoveries helped to understand how the brain develops and how the brain ages.

In the past decade, many studies have shown that neurogenesis in the human brain occurs in a variety of locations and is necessary for cognitive health. Scientists have found that this is especially true in the hippocampus, which is essential for learning and memory.

Neurogenesis in the brain is a complex process that involves a number of stages, including cell proliferation, differentiation, and migration. It is regulated by a range of extrinsic and intrinsic factors. Specifically, many transcription factors regulate neurogenesis in the brain.

The epigenetic regulation of neurogenesis is crucial for maintaining neurogenesis throughout adult life. Over the past decade, a large number of epigenetic genes have been identified that play MPO FA an important role in regulating neurogenesis. These genes have been categorized into three groups: genes that activate the expression of genes involved in self-renewal and proliferation, genes that promote the maintenance of neurons, and genes that specify the fate of newly formed neurons.

Although some studies have shown that MPO deficiency improves neurogenesis after ischemic stroke, the mechanism of how MPO inhibition enhances neurogenesis in the brain is unclear. Nevertheless, we investigated the effect of MPO inhibition on neurogenesis after ischemia in mice using a specific irreversible inhibitor, 4-aminobenzoic acid hydrazide (ABAH).

Mice that were treated with ABAH showed increased number of bromodeoxyuridine (BrdU)-positive cells expressing markers for neural stems cells, astrocytes, and neuroprogenitor cells in the ipsilateral subventricular zone (SVZ), anterior SVZ, striatum, and cortex compared with controls. In addition, ABAH increased levels of brain-derived neurotrophic factor, phosphorylation of cAMP response element-binding protein (Ser133), acetylated H3, and NeuN in the SVZ and striatum.

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