Journal
THROMBOSIS RESEARCH
Volume 131, Issue 3, Pages 230-237Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.thromres.2012.12.009
Keywords
Dendritic cells; Bisoprolol; beta-arrestin 2; CCR7; PI3K; Atherosclerosis
Categories
Funding
- Health Bureau of Shanghai [2009216, 20124253]
- Key Disciplines of Pudong New Area Health Systems in China [PWZxk2010-05]
- Medical Foundation of Tongji University
- Science-technology Supporting and Social Developing Foundation of Zhenjiang in China [2011024]
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The effect of bisoprolol on dendritic cell (DC) migration was investigated, including the analysis of protein expression, cytokine secretion and activation of the PI3K-pathway. The chemotactic cell numbers in cholesterol-loaded DCs treated with epinephrine were significantly decreased by 26.66+/-6.29% (6 h), 35.67+/-2.91% (12 h) and 29.33+/-1.09% (24 h). This effect was significantly reversed by 46.00+/-10.65% (6 h), 64.25+/-6.77% (12 h) and 55.74+/-5.51% (24 h) when bisoprolol and epinephrine were both present. In cholesterol-loaded DCs, treatment with epinephrine significantly increased AR-beta 1 protein expression by 56.99+/-4.87%, but inhibited beta-arrestin 2 and CCR7 protein expression by 30.51+/-4.22% and 25.31+/-0.04%, respectively. These effects were reversed by bisoprolol by 36.87+/-4.40%, 41.47+/-3.95% and 30.14+/-0.54%, respectively. TNF-alpha and MMP9 levels were decreased by 68.33+/-4.00% and 39.57+/-9.21% in cholesterol-loaded DCs treated with epinephrine. In contrast, when bisoprolol and epinephrine were administered together, the secretion of these proteins was significantly increased by 233.81+/-37.06% and 76.66+/-14.21%, respectively. Treatment with epinephrine decreased PI3K-phosphorylation by 31.88+/-2.79%, 40.24+/-5.69% and 30.93+/-4.66% at 15, 30 and 60 min, respectively, whereas the effect of epinephrine on the expression of phosphorylated PI3K was reversed by 49.49+/-12.12%, 70.93+/-16.14% and 47.62+/-6.00%, respectively, when cells were treated with both bisoprolol and epinephrine. Wortmannin inhibited the effects of bisoprolol on PI3K-phosphorylation (38.63+/-6.12%), the expression of CCR7 (23.4+/-2.72%), the secretion of TNF-alpha (69.46+/-4.48%) and MMP9 (43.15+/-4.63%), and the number of chemotactic cells (36.84+/-5.22%). This is the first study to establish a signaling pathway, epinephrine-AR-beta 1-beta-arrestin2-PI3K-MMP9/CCR7, which plays a critical role in the migration of DCs. (C) 2012 Elsevier Ltd. All rights reserved.
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