Purinergic receptors in atherosclerosis: implications for pathophysiology and therapeutic strategies

Atherosclerosis is a complex cardiovascular disease characterised by the accumulation of lipids, inflammatory cells, and fibrous elements within arterial walls, leading to plaque formation and increased risk of cardiovascular events. Recent evidence highlights the pivotal roles of purinergic receptors in mediating the inflammatory and cellular processes associated with atherosclerosis. This review examines the roles of purinergic receptors in the pathophysiology of atherosclerosis, with a particular focus on the P1 subtype (A2A and A3 receptors), the P2X subtype (P2X4 and P2X7 receptors), and the P2Y subtype (P2Y2, P2Y11, and P2Y12 receptors). The A2A and A3 receptors are involved in modulating vascular inflammation, endothelial cell function, and vascular smooth muscle cell calcification. P2X4 has been implicated in the production of pro-inflammatory cytokines and the promotion of plaque inflammation, whereas P2X7 contributes to vascular inflammation, plaque progression, and rupture. The P2Y2 receptor plays critical roles in regulating vascular inflammation and calcification, smooth muscle cell migration, and plaque growth. Furthermore, the P2Y11 receptor has been shown to modulate endothelial cell inflammation, while P2Y12 is associated with lipid accumulation, foam cell formation, vascular smooth muscle cell migration, and plaque development. By synthesising current knowledge on the involvement of purinergic signalling in atherosclerosis, this review discusses potential therapeutic targets for intervention. Specifically, P2Y receptor antagonists present promising avenues for reducing inflammation and improving vascular function in atherosclerotic patients. However, despite the advancements in understanding purinergic receptor functions, challenges remain in translating this knowledge into clinical practice. Further research is essential to unravel the intricate signalling pathways of these receptors and to develop effective biomarker strategies and therapeutic interventions aimed at combatting atherosclerosis and its associated complications.