Adenosine Modulates HIF-1 alpha, VEGF, IL-8, and Foam Cell Formation in a Human Model of Hypoxic Foam Cells

Objective-Foam cells formation by oxidized low-density lipoprotein (oxLDL) accumulation in macrophages is crucial for development of atherosclerosis. Hypoxia has been demonstrated in atherosclerosis and hypoxia-inducible factor-1 (HIF-1) has been shown to promote intraplaque angiogenesis and foam cells (FC) development. As hypoxia induces HIF-1α stabilization and adenosine (ado) accumulation, we investigated whether this nucleoside regulates HIF-1α in FC. Methods and results-Ado, under hypoxia, stimulates HIF-1α accumulation by activating all adenosine receptors (ARs). HIF-1α modulation involved extracellular signal-regulated kinase 1/2 (ERK 1/2), p38 mitogen-activated protein kinase (p38 MAPK) and protein kinase B (Akt) phosphorylation in the case of A1, A2A, A2B and ERK 1/2 phosphorylation in the case of A3 receptors. Ado, through the activation of A3 and A2B receptors, stimulates vascular endothelial growth factor (VEGF) secretion in a HIF-1α dependent way. Furthermore ado, through the A2B subtype, induces an increase of Interleukin-8 (IL-8) secretion in a ERK 1/2, p38 and Akt kinases-dependent but not HIF-1α-mediated way. Finally, ado stimulates FC formation and this effect is strongly reduced by A3 and A2B blockers and by HIF-1α silencing. Conclusions-This study provides the first evidence that A3, A2B or mixed A3/A2B antagonists may be useful to block important steps in the atherosclerotic plaque development ado-induced.