Selected Publication:

SHR Neuro Cancer Cardio Lipid Metab Microb

Peikert, A; König, S; Suchanek, D; Rofa, K; Schäfer, I; Dimanski, D; Karnbrock, L; Bulatova, K; Engelmann, J; Hoppe, N; Wadle, C; Heidt, T; Albrecht, P; von, Garlen, S; Härdtner, C; Hilgendorf, I; Wolf, D; von, Zur, Mühlen, C; Bode, C; Zirlik, A; Duerschmied, D; Merz, J; Stachon, P.
P2X₄ deficiency reduces atherosclerosis and plaque inflammation in mice.
Sci Rep. 2022; 12(1):2801 Doi: 10.1038/s41598-022-06706-6 [OPEN ACCESS]
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Leading authors Med Uni Graz

Peikert Alexander

Co-authors Med Uni Graz

Zirlik Andreas

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Abstract:

Extracellular adenosine-5'-triphosphate (ATP) acts as an import signaling molecule mediating inflammation via purinergic P2 receptors. ATP binds to the purinergic receptor P2X₄ 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-P2X₄-axis in atherosclerosis. Expression of P2X₄ 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 P2X₄ in atherosclerosis, P2X₄-deficient mice were crossed with low-density lipoprotein receptor-deficient mice and fed high cholesterol diet. After 16 weeks, P2X₄-deficient mice developed smaller atherosclerotic lesions compared to P2X₄-competent mice. Furthermore, intravital microscopy showed reduced ATP-induced leukocyte rolling at the vessel wall in P2X₄-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 P2X₄-deficient mice. Moreover, bone marrow derived macrophages isolated from P2X₄-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, P2X₄-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 P2X₄ 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, P2X₄ deficiency reduced experimental atherosclerosis, plaque inflammation and inflammasome priming, pointing to P2X₄ as a potential therapeutic target in the fight against atherosclerosis.

Find related publications in this database (using NLM MeSH Indexing)

Adenosine Triphosphate - metabolism

Animals - administration & dosage

Atherosclerosis - genetics, pathology

Blood Vessels - drug effects, pathology

Chemokine CCL2 - genetics

Chemokine CXCL1 - genetics

Cholesterol - pharmacology

Diet, High-Fat - adverse effects

Endarterectomy, Carotid - administration & dosage

Humans - administration & dosage

Inflammation - genetics, pathology

Interleukin-6 - genetics

Macrophages - metabolism, pathology

Mice - administration & dosage

Mice, Knockout - administration & dosage

NLR Family, Pyrin Domain-Containing 3 Protein - genetics

Plaque, Atherosclerotic - genetics, pathology

Receptors, LDL - genetics

Receptors, Purinergic P2X4 - genetics

Signal Transduction - genetics

Tumor Necrosis Factor-alpha - genetics

Vascular Cell Adhesion Molecule-1 - genetics

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