Whether adenosine may positively affect cardiac repair is still a matter of debate. We previously reported that adenosine beneficially regulates inflammation, extracellular matrix turnover and angiogenesis, all processes involved in cardiac repair. Here, using a combination of in silico, in vitro, and in vivo approaches, we investigated whether adenosine affects endothelial progenitor cells (EPC), other key players of cardiac repair.Methods
In silico: gene expression data from adenosine-treated EPC were obtained by microarrays. Gene-gene functional similarity was estimated with Gene Ontology-based information. In vitro: early endothelial progenitor cells (EPC) were obtained from peripheral blood mononuclear cells of healthy volunteers. In vivo: 18 rats underwent permanent occlusion of the left anterior descending coronary artery (LAD) and were treated by NaCl (n = 6), CADO (stable analog of adenosine, n=6) and CADO with 8-SPT (pan-antagonist of adenosine receptors, n=6). Rats were injected ip twice daily for 2 months. 6 additional rats were sham-operated.Results
Computational systems-based approaches allowed the implementation of a new integrative predictive model based on the combination of gene expression data and gene ontology-based similarity information. This model predicted that adenosine may regulate the expression of several members of the chemokine family in EPC (AUC = 0.92). This prediction was validated in cultured EPC, in which adenosine regulated the expression of multiple chemokines and chemokine receptors. Among these, CXCR4 was significantly up-regulated (3-fold increase, P < 0.001). Pharmacology and RNA interference experiments implicated the A2B adenosine receptor in this effect. Adenosine stimulated EPC migration towards stromal cell-derived factor-1α and conditioned medium from cardiac fibroblasts. This effect was blocked by anti-CXCR4 neutralizing antibodies. In rats, 2 months after induction of myocardial infarction, the amount of EPC recruited to the heart was enhanced by CADO treatment and inhibited by 8-SPT. This was accompanied by increased vascularization in the border zone.Conclusion
Systems-based approaches identified adenosine as a major regulator of EPC. Adenosine up-regulates CXCR4 expression in EPC and stimulates their recruitment to the infarcted heart. Together with previous observations, these results suggest that adenosine has the potential to enhance cardiac repair.