Does myeloperoxidase from neutrophils impair nitric oxide signaling and promote a prothrombotic vascular surface?

Myeloperoxidase (MPO) is a heme-containing enzyme released primarily by activated neutrophils that serves as a potent driver of vascular inflammation and oxidative stress. Extensive research identifies MPO not only as a biomarker of neutrophil activation but also as a direct mediator of endothelial dysfunction and cardiovascular risk.

Clinical and effectiveness evidence

MPO levels serve as a robust indicator of systemic inflammation and are predictive of adverse outcomes in cardiovascular disease.

• Predictive Value: In a study of 604 patients presenting with chest pain, elevated baseline MPO levels were significantly associated with an increased risk of major adverse cardiac events (MACE) at 30 days and six months (p < 0.001).
• Vascular Dysfunction: Clinical assessments using flow-mediated dilation (FMD) have shown that higher serum MPO concentrations correlate with impaired brachial artery reactivity, a hallmark of systemic endothelial dysfunction.

Mechanistic explanations

MPO promotes vascular damage through a complex interplay of oxidative catalysis and signaling disruption:

• Nitric Oxide Depletion: MPO serves as a "sink" for nitric oxide (NO). It consumes NO directly as a substrate and generates hypochlorous acid (HOCl), which scavenges NO at near-diffusion-limited rates (~10⁷ M⁻¹s⁻¹). This rapidly reduces NO bioavailability, preventing the activation of soluble guanylate cyclase (sGC) required for vasodilation.
• Endothelial Injury: MPO binds to the vascular wall and the subendothelial matrix. Once localized, it produces HOCl and other reactive species that induce endothelial cell apoptosis, oxidize adhesive proteins like fibronectin, and destabilize the protective glycocalyx layer.
• Prothrombotic Transition: MPO creates a procoagulant environment by oxidizing low-density lipoprotein (LDL) into its highly atherogenic forms and enhancing platelet activation through actin reorganization. Furthermore, during NETosis, MPO is released as part of neutrophil extracellular traps (NETs), which provide a physical scaffold for platelet entrapment and thrombus stabilization.

Bottom line

MPO is a critical mediator of vascular injury that impairs nitric oxide signaling, destroys endothelial integrity via oxidative stress, and converts the vascular surface into a prothrombotic state. Its measurement provides specific insight into neutrophil-driven inflammatory processes that directly contribute to plaque instability and thrombotic risk.