P2X7 receptor in cardiovascular disease: The heart side

Abstract

Summary The P2X7 receptor is a ligand‐gated purinergic receptor activated by extracellular ATP. The receptor is highly expressed in immune cells and in the brain, and, upon activation, the P2X7 receptor allows a cation flux, leading to the distinct activation of intracellular signalling pathways as the secretion of pro‐inflammatory cytokines, and modulation of cell survival. Through these molecular mechanisms, P2X7 is known to play important roles in physiology and pathophysiology of a wide spectrum of diseases, including cancer, inflammatory diseases, neurological, respiratory and more recently cardiovascular diseases. Recent studies demonstrated that the P2X7 could modulate the assembly of the NLRP3 inflammasome, leading to the secretion of pro‐inflammatory factors and worsen the cardiac disease phenotypes. This review discusses the critical molecular function of P2X7 in the modulation of the onset, progression and resolution of cardiovascular diseases and analyses the putative future use of P2X7‐based therapies that modulate the IL‐1β secretion arm and direct P2X7 antagonists.

Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success

“…In case of danger, damage and/or stress, however, very high levels of ATP are translocated to the extracellular space, acting as important immunomodulatory DAMPs by activating the P2X purinoceptor 7 (P2X 7 ) ( 167 ). P2X 7 activation results in potassium efflux leading to activation of intracellular signaling pathways causing the release of pro-inflammatory cytokines ( 65 ). The most investigated function of P2X 7 in IRI is probably its role in NLRP3 inflammasome assembly and subsequent maturation ( 65 ).…”

“…P2X 7 activation results in potassium efflux leading to activation of intracellular signaling pathways causing the release of pro-inflammatory cytokines ( 65 ). The most investigated function of P2X 7 in IRI is probably its role in NLRP3 inflammasome assembly and subsequent maturation ( 65 ).…”

Purinergic System Signaling in Metainflammation-Associated Osteoarthritis

“…This results in a massive efflux of K + across the porous cytoplasmic membrane ( 245 ). The P2X7 receptor mediates NLRP3 inflammasome activation in different inflammatory diseases and conditions, and is highly expressed in leukocytes and in other cell types ( 246 – 248 ). Pannexin-1 forms hemichannels across the plasma membrane permeable to ATP, releasing it to the extracellular milieu ( 249 ).…”

Design, Synthesis, and in vitro Evaluation of P2X7 Antagonists

“…Moreover, P2X7 is present in a wide variety of cells in the human body [7] and has been associated with multiple diseases, including inflammatory [8] and CNS disorders, [9,10] inflammatory pain, rheumatoid arthritis [11] and cardiovascular diseases. [12] The activation of P2X7 requires high extracellular ATP concentrations (1 mM), in contrast to concentrations < 100 μM needed to activate other P2X subtypes, and leads to the formation of a large conductance pore rather than to desensitization. [9] This non-selective macropore facilitates the influx of large ions and hydrophilic solutes (up to 900 Da) that may cause cell death due to apoptosis and necrosis.…”