P2X7 Receptors: An Untapped Target for the Management of Cardiovascular Disease

Abstract

Chronic low-grade inflammation contributes to the development of several diseases, including cardiovascular disease. Adequate strategies to target inflammation in cardiovascular disease are in their infancy and remain an avenue of great interest. The purinergic receptor P2X7 is a ubiquitously expressed receptor that predominately mediates inflammation and cellular death. P2X7 is a ligand-gated cation channel that is activated in response to high concentrations of extracellular ATP, triggering the assembly and activation of the NLRP3 (nuclear oligomerization domain like receptor family pyrin domain containing 3) inflammasome and subsequent release of proinflammatory cytokines IL (interleukin)-1β and IL-18. Increased P2X7 activation and IL-1β and IL-18 concentrations have been implicated in the development of many cardiovascular conditions including hypertension, atherosclerosis, ischemia/reperfusion injury, and heart failure. P2X7 receptor KO (knockout) mice exhibit a significant attenuation of the inflammatory response, which corresponds with reduced disease severity. P2X7 antagonism blunts blood pressure elevation in hypertension and progression of atherosclerosis in animal models. IL-1β and IL-18 inhibition has shown efficacy in clinical trials reducing major adverse cardiac events, including myocardial infarction, and heart failure. With several P2X7 antagonists available with proven safety margins, P2X7 antagonism could represent an untapped potential for therapeutic intervention in cardiovascular disorders.

Keywords: cardiovascular diseases; heart failure; infant; inflammation; interleukins.

Figure 1.

P2X7 and hypertension. Hypertensive stimuli induce an upregulation of P2RX7 (P2X7 receptor) surface expression,^,, as well as directly and indirectly cause increases in extracellular ATP (eATP) in the renal interstitial fluid.^, Elevated ATP activates P2RX7 promoting cellular death, causing the release of proinflammatory cytokines, inducing renal vasoconstriction, and promoting sodium retention. P2X7-induced renal vasoconstriction causes tissue hypoxia, where along with inflammatory cytokines and reactive oxygen species, it causes inflammation, fibrosis, and glomerular dysfunction.^,– Together, renal fibrosis, increased sodium retention, and renal vasoconstriction promote a rise in blood pressure (BP) that can increase systemic circulating ATP concentrations. The resulting P2X7 activation promotes endothelial cell apoptosis,^, vascular remodeling, and ultimately endothelial dysfunction,^, which further exacerbates the increase in BP. IL indicates interleukin.

Figure 2.

P2X7 and atherosclerosis. Oscillating flow or high glucose or palmitate promote P2RX7 (P2X7 receptor) surface expression, elevate extracellular ATP (eATP),^, and decrease CD39 (cluster of differentiation 39) expression^, in the endothelium at sites prone to develop atherosclerosis, creating an environment suitable for enhanced P2X7 activation. Endothelial P2X7 activation promotes leukocyte recruitment, adhesion, and transmigration into the developing plaque through production of inflammatory cytokines and increased adhesion molecule (AM) expression on endothelial cells.^,,, P2X7-dependent IL (interleukin)-1β production from vascular smooth muscle cells (VSMCs), macrophages, and fibroblasts promotes MMP9 (matrix metalloprotease 9) release from macrophages and VSMCs.^,– MMP9 destabilizes the plaque, making it vulnerable to rupture,^, whereas P2X7 activation on myeloid cells induces the release of TF (tissue factor) promoting thrombus formation.^, Cav-1 indicates caveolin-1; IL-1R, interleukin-1 receptor; and ROS, reactive oxygen species.