Neutrophil extracellular traps (NETs) in cardiovascular diseases: From molecular mechanisms to therapeutic interventions

Abstract

Neutrophil extracellular traps (NETs), which are net-like structures composed of DNA, histones, and antimicrobial proteins, in particular myeloperoxidase (MPO) and elastase, have been demonstrated in bacterial, viral, protozoal, and fungal infections as a potent innate immunity mechanism of pathogen elimination associated with enhanced inflammation. Growing evidence indicates the contribution of NETs formation (NETosis), driven by protein-arginine deiminase type 4, to thrombosis, ischemia, and atherosclerosis. NETs are considered new players involved in the development and progression of cardiovascular diseases (CVDs), including coronary artery disease (CAD) and its acute manifestations in particular acute myocardial infarction (MI), peripheral artery disease (PAD) along with ischemic stroke, heart failure, aortic stenosis, and atrial fibrillation (AF). Formation of NETs and elevated levels of their circulating markers, e.g. citrullinated histone 3 and MPO-DNA complexes, have been observed in chronic and acute manifestations of CVD. NETs accumulation was associated with plaque rupture, infarct size, and impaired myocardial function. NETs have been identified within human stenotic aortic valves, like in atherosclerotic plaques and arterial thrombi. Moreover, circulating NETs markers in association with prothrombotic markers, including fibrin clot properties, predicted adverse clinical events in AF. Several NETs inhibitors, including recombinant human DNase, an enzyme degrading NETs, reactive oxygen species scavengers, together with antithrombotic and antiplatelet drugs, have been shown to reduce uncontrolled NETosis. This review summarizes the current evidence on the role of NETosis in CVDs, its significance as a risk factor for clinical outcomes, and finally, the potential of NETs as a target for future therapeutic interventions.

Keywords: NETs; atherosclerosis; atrial fibrillation; myocardial infarction; stroke.