Myeloperoxidase: a potential therapeutic target for coronary artery disease

ABSTRACT

Introduction

Coronary artery disease (CAD) poses significant morbidity and mortality globally. Despite significant advances in treatment interventions, residual cardiovascular risks remain unchecked. Recent clinical trials have shed light on the potential therapeutic benefits of targeting anti-inflammatory pathways. Myeloperoxidase (MPO) plays an important role in atherosclerotic plaque formation and destabilization of the fibrous cap; both increase the risk of atherosclerotic cardiovascular disease and especially CAD.

Areas covered

This article examines the role of MPO in the pathogenesis of atherosclerotic CAD and the mechanistic data from several key therapeutic drug targets. There have been numerous interesting studies on prototype compounds that directly or indirectly attenuate the enzymatic activities of MPO, and subsequently exhibit atheroprotective effects; these include aminobenzoic acid hydrazide, ferulic acid derivative (INV-315), thiouracil derivatives (PF-1355 and PF-06282999), 2-thioxanthines derivative (AZM198), triazolopyrimidines, acetaminophen, N-acetyl lysyltyrosylcysteine (KYC), flavonoids, and alternative substrates such as thiocyanate and nitroxide radical.

Expert opinion

Future investigations must determine if the cardiovascular benefits of direct systemic inhibition of MPO outweigh the risk of immune dysfunction, which may be less likely to arise with alternative substrates or MPO inhibitors that selectively attenuate atherogenic effects of MPO.

KEYWORDS:

• Myeloperoxidase
• coronary artery disease
• inflammation
• oxidative Stress

Article highlights

• Myeloperoxidase (MPO) has been mechanistically linked to the development and progression of coronary artery disease (CAD) and other atherosclerotic cardiovascular diseases.

• MPO plays a role in pathogenesis of atherosclerosis by oxidizing low-density lipoprotein, modifying high-density lipoprotein, promoting endothelial dysfunction, and weakening atherosclerotic plaque.

• A variety of MPO inhibitors that provide atheroprotective effects have been developed and investigated in preclinical studies, including benzoic acid hydrazides, ferulic acid derivative, thiouracil derivatives, 2-thioxanthine derivatives, triazolopyrimidines, acetaminophen, N-acetyl lysyltyrosylcysteine amide, flavonoids, ceruloplasmin and alternative substrates.

• Promising MPO inhibitors, such as PF-1355, AZM198, and alternative substrates, including nitroxide radical and thiocyanate, have been shown to reduce atherosclerotic burden, stabilize atherosclerotic plaque, and prevent cardiac complications from CAD in in vitro and animal studies.

• Direct systemic inhibition of MPO may be associated with immune dysfunction, which needs to be monitored along with potential cardiovascular benefits.

• Soon, there will be a variety of novel exogenous and endogenous MPO inhibitors developed and demonstrated in preclinical studies, whereas PF-1355, AZM198, nitroxide radical, and thiocyanate will be further investigated in animal models and potentially clinical studies.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

W Tang is funded by grants from the National Institutes of Health, National Heart, Lung, and Blood Institute [R01HL103931; R01HL126827] and National Institute of Diabetes and Digestive and Kidney Diseases [R01DK106000].