Myeloperoxidase (MPO) which contains iron exists within neutrophils and monocytes lysosomal granules to conduct vital roles in both immune defense and response to oxidative stress.
- Molecular function: The enzyme Myeloperoxidase (MPO) transforms hydrogen peroxide (H₂O₂) into strong oxidants such as hypochlorous acid (HOCl) through its reaction with chloride ions (Cl⁻).
- Main function: The enzyme kills pathogens but damages host tissues through oxidation.
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Introduction to MPO
- Molecular properties: MPO is a copper-green heme enzyme belonging to the peroxidase family.
- Source: Neutrophils generate these enzymes as their primary source while certain monocytes contribute to their production which is then stored in lysosomal granules.
- Function: The system employs hydrogen peroxide (H₂O₂) to drive the production of powerful oxidants like hypochlorous acid (HOCl) while playing a role in bactericidal and defensive functions.
MPO and Inflammatory Atherosclerosis
MPO expression but their MPO expression becomes substantial as the disease develops to later stages. The electrostatic interactions between MPO and ECs lead to MPO internalization into vascular wall atherosclerotic lesions through endocytosis. MPO targets and alters apolipoprotein AI (apoA-I) within HDL which reduces the protective properties HDL provides against atherosclerosis.
Role of MPO in Atherosclerosis
Atherosclerosis is a chronic inflammatory disease. The main roles of MPO in this process include:
Oxidized Low-density Lipoprotein (LDL)
The chemical reaction between MPO and HOCl results in oxLDL formation and foam cell production which represents one of the initial stages in plaque development within atherosclerosis.
Endothelial Dysfunction
MPO destroys nitric oxide (NO) which weakens its vasodilatory function and causes endothelial dysfunction.
Promote Smooth Muscle Cell Proliferation and Migration
The activation of oxidative signaling by MPO triggers vascular smooth muscle cell movement to the intima and leads to plaque formation.
Unstable Plaque Formation and Rupture
MPO induces collagen degradation alongside matrix metalloproteinase (MMP) activation which results in a thinner plaque fibrous cap that ruptures more easily.
The Role of MPO in Inflammatory Response
As the defining enzyme of inflammatory reactions MPO performs essential roles during both infectious processes and sterile inflammation scenarios.
Enhance Oxidative Stress
MPO generates lethal substances like HOCl and chloramines which kill microorganisms. The body creates reactive oxygen/nitrogen species which inflict damage to host tissues and lead to persistent inflammation. MPO enables the conversion of hydrogen peroxide together with chloride ions into hypochlorous acid that functions as an intense oxidizing and bactericidal agent. Elevated activity levels of MPO lead to increased oxidative stress at the site of inflammation.
Promote Phagocytosis and NETs Formation
The formation of neutrophil extracellular traps (NETs) is strongly linked to MPO activity. NETs function to trap pathogens yet their overproduction leads to damage in body tissues.
Activate Inflammatory Signaling Pathways
The oxidation of proteins and lipids by MPO activates NF-κB and MAPK inflammatory pathways. Pro-inflammatory cytokines including IL-1β, TNF-α, and IL-6 lead to the establishment of a positive feedback system. MPO creates specific oxidants such as nitric oxide which affects cell signaling and regulates inflammatory mediator release thereby establishing the level and timeframe of inflammation.
Promoting Cell Apoptosis and Necrosis
Oxidative stress produced by MPO triggers apoptosis in endothelial cells and macrophages while sustaining inflammatory responses.
Leukocyte Activation
The release of MPO during inflammation facilitates leukocyte infiltration and activation which positions them to contribute to the inflammatory response. The process aids in pathogen removal yet risks tissue damage when excessively activated.
Treatment Prospects
- Biomarkers: The risk of coronary heart disease and myocardial infarction links with increased MPO levels which show potential as early diagnostic markers.
- Targeted therapy research: Current research on MPO inhibitors including AZD5904 suggests they might be developed into a new treatment approach for cardiovascular diseases.
- Antioxidant intervention: Antioxidants diminish inflammation and slow down atherosclerosis by eliminating ROS or inhibiting MPO activity.
References
- Frangie, C., et al. Role of myeloperoxidase in inflammation and atherosclerosis. Biomedical reports. 2022, 16(6): 53.
- Kargapolova, Y., et al. The enzymatic and non-enzymatic function of myeloperoxidase (MPO) in inflammatory communication. Antioxidants. 2021, 10(4): 562.
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