Abstract 1217: Adenosine Promotes Angiogenic Switch in Human Macrophages
Purpose: Post-infarct left ventricular remodeling is a leading cause of heart failure. The transition from adaptive to maladaptive remodeling is not fully understood. However it appears that angiogenesis may induce cardiac repair and positively affect ventricular remodeling. Large amounts of adenosine are produced locally in the heart following myocardial infarction (MI). An emerging concept is that adenosine has both anti-inflammatory and pro-angiogenic properties. We report here the characterization of the angiogenic switch induced by adenosine in human macrophages isolated from healthy volunteers and patients with acute MI.
Methods: Primary monocytes isolated from human peripheral blood mononuclear cells were differentiated by 50 ng/mL macrophage-colony stimulating factor for 7 days. Macrophages were preincubated for 15 minutes with adenosine (10 μM) or adenosine analogs (0.1 to 10 μM) before LPS treatment (100 ng/mL for 24 hours). ELISA and real-time quantitative PCR were used to measure levels of TNF-α, Matrix Metalloproteinase (MMP)-9, Vascular Endothelial Growth Factor (VEGF), and adenosine receptors.
Results: In LPS-stimulated macrophages, adenosine induced a 83% decrease of TNF-α secretion (p<0.005). This decrease was replicated by the A3 agonist Cl-IB-MECA, suggesting involvement of the A3 receptor. Adenosine increased VEGF secretion both alone (3.8-fold, p<0.01) and in synergy with LPS (28-fold, p<0.0002). Adenosine also increased MMP-9 expression. The effects of adenosine on VEGF and MMP-9 were replicated by the A2a agonist C141 and blocked by the A2a (SCH58261) and A2b (MRS1754) antagonists, suggesting involvement of the A2a/A2b receptors. Interestingly, the effects of adenosine on TNF-α and VEGF expression were more pronounced in macrophages isolated from patients with acute MI than in cells from healthy controls.
Conclusion: Adenosine induces an angiogenic switch in human macrophages characterized by decreased TNF-α secretion and enhanced MMP-9 and VEGF expression. This switch is more robust in patients with acute MI. Thus, adenosine regulating agents may represent a new approach to stimulate angiogenesis.