Abstract
Neutrophils and neutrophil extracellular traps (NETs) have a robust relationship with
atherothrombotic disease risk, which led to the idea that interfering with the release
of NETs therapeutically would ameliorate atherosclerosis. In human studies, acute
coronary events and the pro-thrombotic state cause markedly elevated levels of circulating
deoxyribonucleic acid (DNA) and chromatin, suggesting that DNase I might produce cardiovascular
benefit. DNase I reproduced the phenotype of peptidylarginine deiminase 4 (PAD4) deficiency
and showed a significant benefit for atherothrombotic disease in experimental mouse
models. However, the mechanisms of benefit remain unclear. Insights into the mechanisms
underlying NET release and atherogenic inflammation have come from transgenic mouse
studies. In particular, the importance of neutrophil NET formation in promoting atherothrombotic
disease has been shown and linked to profound pro-inflammatory and pro-thrombotic
effects, complement activation and endothelial dysfunction. Recent studies have shown
that myeloid deficiency of PAD4 leads to diminished NET formation, which in turn protects
against atherosclerosis burden, propagation of its thrombotic complications and notably
macrophage inflammation in plaques. In addition, oxidative stress and neutrophil cholesterol
accumulation have emerged as important factors driving NET release, likely involving
mitochondrial reactive oxidants and neutrophil inflammasome activation. Further elucidation
of the mechanisms linking hyperlipidaemia to the release of NETs may lead to the development
of new therapeutics specifically targeting atherogenic inflammation, with likely benefit
for cardiovascular diseases.
Keywords
neutrophil - NETosis - atherogenic inflammation - atherothrombotic disease
