Extracellular ATP Induces Vascular Inflammation and Atherosclerosis via Purinergic Receptor Y ₂ in Mice

Abstract

Objective— A solid body of evidence supports a role of extracellular ATP and its P2 receptors in innate and adaptive immunity. It promotes inflammation as a danger signal in various chronic inflammatory diseases. Thus, we hypothesize contribution of extracellular ATP and its receptor P2Y 2 in vascular inflammation and atherosclerosis. Approach and Results— Extracellular ATP induced leukocyte rolling, adhesion, and migration in vivo as assessed by intravital microscopy and in sterile peritonitis. To test the role of extracellular ATP in atherosclerosis, ATP or saline as control was injected intraperitoneally 3× a week in low-density lipoprotein receptor −/− mice consuming high cholesterol diet. Atherosclerosis significantly increased after 16 weeks in ATP-treated mice (n=13; control group, 0.26 mm2; ATP group, 0.33 mm2; P =0.01). To gain into the role of ATP-receptor P2Y 2 in ATP-induced leukocyte recruitment, ATP was administered systemically in P2Y 2 -deficient or P2Y 2 -competent mice. In P2Y 2 -deficient mice, the ATP-induced leukocyte adhesion was significantly reduced as assessed by intravital microscopy. P2Y 2 expression in atherosclerosis was measured by real-time polymerase chain reaction and immunohistochemistry and demonstrates an increased expression mainly caused by influx of P2Y 2 -expressing macrophages. To investigate the functional role of P2Y 2 in atherogenesis, P2Y 2 -deficient low-density lipoprotein receptor −/− mice consumed high cholesterol diet. After 16 weeks, P2Y 2 -deficient mice showed significantly reduced atherosclerotic lesions with decreased macrophages compared with P2Y 2 -competent mice (n=11; aortic arch: control group, 0.25 mm 2 ; P2Y 2 -deficient, 0.14 mm2; P =0.04). Mechanistically, atherosclerotic lesions from P2Y 2 -deficient mice expressed less vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 RNA. Conclusions— We show that extracellular ATP induces vascular inflammation and atherosclerosis via activation of P2Y 2 .

P2X7 Receptor Induces Tumor Necrosis Factor-α Converting Enzyme Activation and Release to Boost TNF-α Production

“…ATP treatment did not change the increase of infiltrated peritoneal Gr-1/Mac-1-positive cells (Figure 3C). This result contrast with previous publications showing that ATP increases granulocyte infiltration to the peritoneum (20, 21); however, in such studies, ATP was used at lower concentration and without endotoxin that might explain the differences.…”

Atheroprone flow activates inflammation via endothelial ATP-dependent P2X7-p38 signalling

“… 7–10 Moreover recent studies have shown that administration of extracellular ATP to ApoE − / − mice exacerbated atherosclerosis by increasing leukocyte adhesion and migration. 9 Furthermore, inflammatory stimuli such as LPS 42 , TNF, 35 hypoxia, 36 and high glucose/palmitate 10 all increase extracellular ATP release from endothelial cells, further supporting a role of extracellular ATP in endothelial inflammatory responses. Thus we suggest that mechanical shear-dependent upregulation of P2X7 at atheroprone sites may be important in the initiation of atherosclerosis by transducing extracellular ATP into pro-inflammatory signalling responses.…”

Altered Energy Metabolism During Early Optic Nerve Crush Injury: Implications of Warburg-Like Aerobic Glycolysis in Facilitating Retinal Ganglion Cell Survival

“…Given that more internal energy failed to produce more surviving RGCs, we questioned whether supplying extrinsic ATP would confer any benefit for RGC survival. ATP was injected at a relatively high dose (50 mg/kg) [37,38] and a low dose (5 lmol/kg; *2.865 mg/kg) [39]. Intraperitoneal injections did not have a significant effect on RGC survival in either injured or intact eyes (Fig.…”