Exploring Neutrophil Extracellular Traps in Cardiovascular Pathologies: The Impact of Lipid Profiles, PAD4, and Radiation.

Abstract

Neutrophil extracellular traps (NET) have emerged as critical players in the pathogenesis of atherosclerosis and other cardiovascular diseases (CVD). These web-like structures, composed of DNA, histones, and granule proteins released by neutrophils, contribute significantly to both inflammation and thrombosis. This manuscript offers a comprehensive review of the recent literature on the involvement of NET in atherosclerosis, highlighting their interactions with various pathophysiological processes and their potential as biomarkers for CVD. Notably, the impact of radiation on NET formation is explored, emphasising how oxidative stress and inflammatory responses drive NET release, contributing to plaque instability. The role of histones, particularly citrullinated histones, in endothelial dysfunction and plaque progression is discussed, highlighting their significance in the pathophysiology of atherosclerosis. Furthermore, the complex relationship between lipoproteins and NET formation is examined, with a focus on how elevated low-density lipoprotein (LDL) and decreased high-density lipoprotein (HDL) levels facilitate NET release, thus promoting vascular inflammation and plaque instability. The influence of cholesterol on NET formation is also explored, underscoring its contribution to plaque development and stability. The role of Peptidylarginine deiminase 4 (PAD4) in the regulation of NETosis is reviewed, with attention given to how PAD4-driven citrullination of histones affects atherosclerosis progression. Moreover, the manuscript examines the potential of NET components-such as double-stranded DNA, myeloperoxidase-DNA complexes, and citrullinated histone H3-as biomarkers for assessing disease severity and predicting adverse cardiovascular events, including ST-elevation myocardial infarction (STEMI) and stroke. Elevated levels of these biomarkers correlate with worse clinical outcomes, suggesting their utility in guiding therapeutic interventions. In contrast to the existing body of work, this review highlights the novelty of integrating recent findings on NET interactions with lipid metabolism, histone modifications, and PAD4 activity in the context of atherosclerosis. Overall, NET plays an integral role in the inflammatory and thrombotic processes underpinning atherosclerosis, and their components hold promise as both diagnostic markers and therapeutic targets in cardiovascular disease management.