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-1alpha stabilization and adenosine (ado) accumulation, we investigated whether this nucleoside regulates HIF-1alpha in FCs. METHODS AND RESULTS: Ado, under hypoxia, stimulates HIF-1alpha accumulation by activating all adenosine receptors (ARs). HIF-1alpha 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 A(1), A(2A), A(2B), and ERK 1/2 phosphorylation in the case of A(3) receptors. Ado, through the activation of A(3) and A(2B) receptors, stimulates vascular endothelial growth factor (VEGF) secretion in a HIF-1alpha-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-1alpha-mediated way. Finally, ado stimulates FC formation, and this effect is strongly reduced by A(3) and A(2B) blockers and by HIF-1alpha silencing. CONCLUSIONS: This study provides the first evidence that A(3,) A(2B), or mixed A(3)/A(2B) antagonists may be useful to block important steps in the atherosclerotic plaque development ado-induced.
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-1alpha stabilization and adenosine (ado) accumulation, we investigated whether this nucleoside regulates HIF-1alpha in FCs. METHODS AND RESULTS:Ado, under hypoxia, stimulates HIF-1alpha accumulation by activating all adenosine receptors (ARs). HIF-1alpha 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 A(1), A(2A), A(2B), and ERK 1/2 phosphorylation in the case of A(3) receptors. Ado, through the activation of A(3) and A(2B) receptors, stimulates vascular endothelial growth factor (VEGF) secretion in a HIF-1alpha-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-1alpha-mediated way. Finally, ado stimulates FC formation, and this effect is strongly reduced by A(3) and A(2B) blockers and by HIF-1alpha silencing. CONCLUSIONS: This study provides the first evidence that A(3,) A(2B), or mixed A(3)/A(2B) antagonists may be useful to block important steps in the atherosclerotic plaque development ado-induced.