In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 135, No. 25 ( 2017-06-20), p. 2524-2533
Abstract:
Extracellular adenosine triphosphate (ATP) binds as a danger signal to purinergic receptor P2X 7 and promotes inflammasome assembly and interleukin-1β expression. We hypothesized a functional role of the signal axis ATP–P2X 7 in inflammasome activation and the chronic inflammation driving atherosclerosis. Methods: P2X 7 -competent and P2X 7 -deficient macrophages were isolated and stimulated with lipopolysaccharide, ATP, or both. To assess whether P2X 7 may have a role in atherosclerosis, P2X 7 expression was analyzed in aortic arches from low density lipoprotein receptor -/- mice consuming a high-cholesterol or chow diet. P2X 7 +/+ and P2X 7 −/− low density lipoprotein receptor −/− mice were fed a high-cholesterol diet to investigate the functional role of P2X 7 knockout in atherosclerosis. Human plaques were derived from carotid endarterectomy and stained against P2X 7 . Results: Lipopolysaccharide or ATP stimulation alone did not activate caspase 1 in isolated macrophages. However, priming with lipopolysaccharide, followed by stimulation with ATP, led to an activation of caspase 1 and interleukin-1β in P2X 7 -competent macrophages. In contrast, P2X 7 -deficient macrophages showed no activation of caspase 1 after sequential stimulation while still expressing a basal amount of interleukin-1β. P2X 7 receptor was higher expressed in murine atherosclerotic lesions, particularly by lesional macrophages. After 16 weeks of a high-cholesterol diet, P2X 7 -deficient mice showed smaller atherosclerotic lesions than P2X 7 -competent mice (0.162 cm 2 ±0.023 [n=9], P2X 7 −/− low density lipoprotein receptor −/− : 0.084 cm 2 ±0.01 [n=11], P =0.004) with a reduced amount of lesional macrophages. In accord with our in vitro findings, lesional caspase 1 activity was abolished in P2X 7 −/− mice. In addition, intravital microscopy revealed reduced leukocyte rolling and adhesion in P2X 7 -deficient mice. Last, we observe increased P2X 7 expression in human atherosclerotic lesions, suggesting that our findings in mice are relevant for human disease. Conclusions: P2X 7 deficiency resolved plaque inflammation by inhibition of lesional inflammasome activation and reduced experimental atherosclerosis. Therefore, P2X 7 represents an interesting potential new target to combat atherosclerosis.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/CIRCULATIONAHA.117.027400
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2017
detail.hit.zdb_id:
1466401-X
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