P2 receptors: new potential players in atherosclerosis

Abstract

Atherosclerosis is a focal inflammatory disease of the arterial wall. It starts with the formation of fatty streaks on the arterial wall that evolve to form a raised plaque made of smooth muscle cells (SMCs), and infiltrating leukocytes surrounding a necrotic core. The pathogenesis of the atherosclerotic lesion is incompletely understood, but it is clear that a dysfunction of the endothelium, recruitment and activation of inflammatory cells and SMC proliferation have a pivotal role. Over recent years receptors for extracellular nucleotides, the P2 receptors, have been recognized as fundamental modulators of leukocytes, platelets, SMCs and endothelial cells. P2 receptors mediate chemotaxis, cytokine secretion, NO generation, platelet aggregation and cell proliferation in response to accumulation of nucleotides into the extracellular milieu. Clinical trials have shown the benefit of antagonists of the ADP platelet receptor(s) in the prevention of vascular accidents in patients with atherosclerosis. Therefore, we anticipate that a deeper understanding of the involvement of P2 receptors in atheroma formation will open new avenues for drug design and therapeutic intervention.

Figure 1

Steps in atheroma formation and progression.

Figure 2

Events in atherosclerotic plaque formation. Injury or activation of endothelial cells allows penetration of molecules (e.g. LDL) from the arterial lumen into the subintimal space. Within this space such molecules may undergo modifications (e.g. oxidation) that unable them to further activate intimal cells, and also accelerate phagocytosis by macrophages (MΦ). Endothelial cell activation also facilitates migration of monocytes from the blood. Monocyte migration is sustained by release of chemotactic factors (e.g. MCP-1) by SMCs. Monocytes differentiate into macrophages and phagocytose oxLDLs and other extracellular lipids. During phagocytosis, macrophages become activated and release cytokines and growth factors. Lipid laden macrophages further differentiate into foam cells that eventually die, releasing their content into the necrotic core of the plaque. The plaque undergoes a continuous remodelling due on the one hand to deposition of extracellular matrix protein and on the other to secretion of MMPs that digest the extracellular matrix. Extracellular matrix proteins are secreted by SMCs. MMPs are secreted by SMCs and macrophages. SMCs under the stimulation with LDL, cytokines and growth factors actively proliferate thus forming the fibrous cap (not shown in the Figure). Some of the products released into the plaque may accelerate damage of the endothelial lining by causing apoptosis of endothelial cells.

Figure 3

Hypothetical role of extracellular ATP and nucleotide receptors in atherosclerotic plaque formation. Endothelial damage or activation causes ATP release both into the blood and the arterial wall. On the endothelial surface ATP is hydrolized to ADP thus triggering platelet aggregation via P2Y₁R and P2Y₁₂R. Activated platelets release further ATP that feed-backs on the endothelium increasing its state of activation. In the subintimal space ATP synergyzes with other agents (e.g. oxLDL or IFNγ released by T helper lymphocytes) to promote macrophage activation. ATP acting at P2YR also contributes with MCP-1 to the formation of a chemoatctic gradient for monocytes and macrophages. Macrophages are recruited from circulation as well as from the arterial wall. Under stimulation with ATP, SMCs proliferate and release MMPs and extracellular matrix proteins. ATP, acting at P2X₇R and presumably also at P2YR triggers IL-1β and TNFα release from activated macrophages. At the same time, a high level of extracellular nucleotide released by activated or damaged cells causes a sustained activation of the P2X₇R, thus accelerating cell death, either by necrosis or apoptosis.