Turning Neutrophil Cell Death Deadly in Hypertensive Vascular Disease.

ABSTRACT

Hypertensive vascular disease (HVD) is a major health burden globally and is a comorbidity commonly associated with other metabolic diseases. Many factors are associated with hypertensive vascular disease including obesity, diabetes, smoking, chronic kidney disease, and sterile inflammation. Increasing evidence points to neutrophils as an important component of the chronic inflammatory response in hypertensive vascular disease. Neutrophils are abundant in the circulation and can respond rapidly upon stimulation to deploy an armament of anti-microbial effector functions. One of the outcomes of neutrophil activation is the generation of Neutrophil Extracellular Traps (NETs), a regulated extrusion of chromatin and proteases. While neutrophils and NETs are well described as components of the innate immune response to infection, recent evidence implicates them in HVD. Endothelial cell activation can trigger neutrophil adhesion, activation, and production of NETs promoting vascular dysfunction, vessel remodeling, and loss of resistance. The regulated release of NETs can be controlled by the pore-forming activities of distinct cell death pathways. The best-characterized pathways in this context are apoptosis, pyroptosis, and necroptosis. In this review, we will discuss how inflammatory cell death signaling and NET formation contribute to hypertensive disease. We also examine novel therapeutic approaches to limit NET production and their future potential as therapeutic drugs in cardiovascular disorders.