Beschreibung:
<jats:p>
<jats:bold>Introduction:</jats:bold>
A solid body of evidence supports a role of extracellular ATP and ist P2-receptors in innate and adaptive immunity. It promotes inflammation as a danger signal in various chronic inflammatory diseases. Hypothesis: We hypothesize contribution of extracellular ATP and its receptor P2Y2 in vascular inflammation and atherosclerosis.Methods: Leukocyte rolling and adhesion after stimulation with ATP was determined with intravitalmicroscopy in P2Y2-competent and P2Y2-deficient mice. Migration was analyzed with peritonitis model. To test the role of extracellular ATP in atherosclerosis, ATP or saline as control was injected intraperitoneally three times a week in LDLR-/- mice consuming high cholesterol diet (HCD). Furthermore, P2Y2-competent or P2Y2-deficient mice consumed a HCD for 16 weeks. Atherosclerosis was determined with immunhistochemistry and lesional expression of inflammatory molecules was measured with realtime PCR.
</jats:p>
<jats:p>
<jats:bold>Results:</jats:bold>
Extracellular ATP induced leukocyte rolling, adhesion, and migration as assessed by intravital microscopy and in sterile peritonitis. Atherosclerosis significantly increased after 16 weeks in ATP-treated mice (n=13; control group 0.26mm2; ATP group 0.33mm2, p=0.01). To gain into the role of ATP-receptor P2Y2 in ATP induced leukocyte recruitment, ATP was administered systemically in P2Y2-deficient or -competent mice. In P2Y2-deficient mice the ATP induced leukocyte adhesion was significantly reduced. P2Y2 expression in atherosclerosis was measured by real-time PCR and immunohistochemistry and demonstrates an increased expression s mainly due to influx of P2Y2-expressing macrophages. To investigate the functional role of P2Y2 in atherogenesis, P2Y2-deficient LDLR-/- mice consumed HCD. After 16 weeks P2Y2-deficient mice showed significantly reduced atherosclerotic lesions with decreased macrophages compared to P2Y2-competent mice (n=11; aortic arch: control group 0.25mm2; P2Y2-deficient 0.14mm2, p=0.04). Mechanistically,atherosclerotic lesions from P2Y2-deficient mice expressed less lesional VCAM-1 and ICAM-1 RNA .
</jats:p>
<jats:p>
<jats:bold>Conclusion:</jats:bold>
We show for the first time that extracellular ATP induces vascular inflammation and atherosclerosis via activation of P2Y2.
</jats:p>