Objective—Foam cell (FC) 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 FC development. As hypoxia induces HIF-1 stabilization and adenosine (ado) accumulation, we investigated whether this nucleoside regulates HIF-1 in FCs.

Methods and Results—Ado, under hypoxia, stimulates HIF-1 accumulation by activating all adenosine receptors (ARs). HIF-1 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, A_2A, A_2B, and ERK 1/2 phosphorylation in the case of A₃ receptors. Ado, through the activation of A₃ and A_2B receptors, stimulates vascular endothelial growth factor (VEGF) secretion in a HIF-1–dependent way. Furthermore, ado, through the A_2B subtype, induces an increase of Interleukin-8 (IL-8) secretion in a ERK 1/2, p38, and Akt kinase–dependent but not HIF-1–mediated way. Finally, ado stimulates FC formation, and this effect is strongly reduced by A₃ and A_2B blockers and by HIF-1 silencing.

Conclusions—This study provides the first evidence that A_3, A_2B, or mixed A₃/A_2B antagonists may be useful to block important steps in the atherosclerotic plaque development ado-induced.