Adenosine modulates HIF-1{alpha}, VEGF, IL-8, and foam cell formation in a human model of hypoxic foam cells.
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.


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.
Gessi
Stefania
S
Chair of Pharmacology, Faculty of Medicine, University of Ferrara, Department of Clinical and Experimental Medicine, Pharmacology Unit, Via Fossato di Mortara 17-19, 44100 Ferrara, Italy.
Fogli
Eleonora
E
Sacchetto
Valeria
V
Merighi
Stefania
S
Varani
Katia
K
Preti
Delia
D
Leung
Edward
E
Maclennan
Stephen
S
Borea
Pier Andrea
PA
D000241:Adenosine / Q000378:metabolism*; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D001391:Azo Compounds; D004396:Coloring Agents; D005487:Foam Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000378:metabolism; D020298:U937 Cells; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D001391:Azo Compounds; D004396:Coloring Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016209:Interleukin-8; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D043704:Receptor, Adenosine A2B; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C099252:oxidized low density lipoprotein; D051057:Proto-Oncogene Proteins c-akt; C011049:oil red O; D000241:Adenosine