P2X7 Receptor-Mediated Inflammation in Cardiovascular Disease

Abstract

Purinergic P2X7 receptor, a nonselective cation channel, is highly expressed in immune cells as well as cardiac smooth muscle cells and endothelial cells. Its activation exhibits to mediate nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome activation, resulting in the release of interleukin-1 beta (IL-1β) and interleukin-18 (IL-18), and pyroptosis, thus triggering inflammatory response. These pathological mechanisms lead to the deterioration of various cardiovascular diseases, including atherosclerosis, arrhythmia, myocardial infarction, pulmonary vascular remodeling, and cardiac fibrosis. All these worsening cardiac phenotypes are proven to be attenuated after the P2X7 receptor inhibition in experimental studies. The present review aimed to summarize key aspects of P2X7 receptor-mediated inflammation and pyroptosis in cardiovascular diseases. The main focus is on the evidence addressing the involvement of the P2X7 receptor in the inflammatory responses to the occurrence and development of cardiovascular disease and therapeutic interventions.

Keywords: P2X7 receptor; arterial hypertension; atherosclerosis; inflammation; myocardial infarction.

FIGURE 1

Mechanisms of P2X₇ receptor’s action in cardiovascular disorders. In pathological stress including hypoxia/ischemia/hyperglycemia, the Toll-like receptors (TLRs) are activated, producing progenitors of inflammatory cytokines such as pro-IL-1β and pro-IL-18. Meanwhile, the P2X7 receptor is activated in response to ATP released through PANX1 and connexins in cardiomyocytes. The openness of P2X7 receptor leads to K⁺ efflux and Ca²⁺ influx, triggering NLRP3 inflammasome assembly (a circular platform consisting of NLR, ASC, and pro–caspase-1). NLRP3 inflammasomes convert pro–caspase-1 into active caspase-1. Caspase-1 cleaves the inactive pro–IL-1β and pro–IL-18 cytokines into active cytokines IL-1β and IL-18, respectively, and cuts GSDM-D into active N-terminal fragment. The active form of GSDM-D induces cell membrane disruption through their pore-forming activity and by promoting pyroptosis and releasing IL-1β and IL-18. The inflammatory response mediated by cytokines and pyroptosis contributes to pathology in atherosclerosis, hypertension, pulmonary hypertension, myocardial infarction, arrhythmia, cardiomyopathy, and autoimmune myocarditis.