P2X4 deficiency significantly reduced atherosclerotic lesion size in the aortic root compared to P2X4-competent mice (0.39 vs 0.49 mm2, p<0.01).
Does P2X4 deficiency reduce atherosclerosis and plaque inflammation in LDLR-deficient mice?
P2X4 deficiency reduces experimental atherosclerosis, plaque inflammation, and inflammasome priming, suggesting P2X4 as a potential therapeutic target for atherosclerosis.
Tasa de eventos absoluta: 0.39% vs 0.49%
valor p: p=<0.01
Abstract Extracellular adenosine-5′-triphosphate (ATP) acts as an import signaling molecule mediating inflammation via purinergic P2 receptors. ATP binds to the purinergic receptor P2X 4 and promotes inflammation via increased expression of pro-inflammatory cytokines. Because of the central role of inflammation, we assumed a functional contribution of the ATP-P2X 4 -axis in atherosclerosis. Expression of P2X 4 was increased in atherosclerotic aortic arches from low-density lipoprotein receptor-deficient mice being fed a high cholesterol diet as assessed by real-time polymerase chain reaction and immunohistochemistry. To investigate the functional role of P2X 4 in atherosclerosis, P2X 4 -deficient mice were crossed with low-density lipoprotein receptor-deficient mice and fed high cholesterol diet. After 16 weeks, P2X 4 -deficient mice developed smaller atherosclerotic lesions compared to P2X 4 -competent mice. Furthermore, intravital microscopy showed reduced ATP-induced leukocyte rolling at the vessel wall in P2X 4 -deficient mice. Mechanistically, we found a reduced RNA expression of CC chemokine ligand 2 (CCL-2), C-X-C motif chemokine-1 (CXCL-1), C-X-C motif chemokine-2 (CXCL-2), Interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) as well as a decreased nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-inflammasome priming in atherosclerotic plaques from P2X 4 -deficient mice. Moreover, bone marrow derived macrophages isolated from P2X 4 -deficient mice revealed a reduced ATP-mediated release of CCL-2, CC chemokine ligand 5 (CCL-5), Interleukin-1β (IL-1β) and IL-6. Additionally, P2X 4 -deficient mice shared a lower proportion of pro-inflammatory Ly6C high monocytes and a higher proportion of anti-inflammatory Ly6C low monocytes, and expressend less endothelial VCAM-1. Finally, increased P2X 4 expression in human atherosclerotic lesions from carotid endarterectomy was found, indicating the importance of potential implementations of this study’s findings for human atherosclerosis. Collectively, P2X 4 deficiency reduced experimental atherosclerosis, plaque inflammation and inflammasome priming, pointing to P2X 4 as a potential therapeutic target in the fight against atherosclerosis.
Peikert et al. (2022) studied Atherosclerosis (n=39). P2X4 deficiency vs. P2X4 competent (P2X4+/+) was evaluated on Intimal lesion size in aortic roots (mm2) (p=<0.01). P2X4 deficiency significantly reduced atherosclerotic lesion size in the aortic root compared to P2X4-competent mice (0.39 vs 0.49 mm2, p<0.01).