HIF-1 alpha expression is associated with an atheromatous inflammatory plaque phenotype and upregulated in activated macrophages.
OBJECTIVE
Angiogenesis and inflammation are important features in atherosclerotic plaque destabilization. The transcription factor hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a key regulator of angiogenesis and is also involved in inflammatory reactions. We studied HIF-1 alpha expression in different atherosclerotic plaque phenotypes.


RESULTS
HIF-1 alpha expression was observed in 18/37 (49%) carotid and in 9/15 (60%) femoral endarterectomy specimens. Expression of HIF-1 alpha was associated with the presence of a large extracellular lipid core (P=0.03) and macrophages (P=0.02). HIF-1 alpha co-localized with vascular endothelial growth factor (VEGF), an important downstream target of HIF-1 alpha. In addition, a strong association was observed between expression levels of HIF-1 alpha and VEGF (P=0.001). The average number of plaque microvessels was higher in plaques with no or minor HIF-1 alpha staining than in plaques with moderate or heavy HIF-1 alpha staining (P=0.03). In human macrophages, lipopolysaccharide activation induced HIF-1 alpha expression. In embryonic fibroblasts derived from wild-type mice, lipopolysaccharide activation induced an increase in HIF-1 alpha mRNA, whereas in Toll-like receptor 4 defective embryonic fibroblasts no effect was observed after lipopolysaccharide stimulation.


CONCLUSIONS
In atherosclerotic plaque, the transcription factor HIF-1 alpha is associated with an atheromatous inflammatory plaque phenotype and with VEGF expression. HIF-1 alpha expression is upregulated in activated macrophages under normoxic conditions.
Vink
Aryan
A
Department of Pathology, University Medical Center Utrecht, Ultrecht, The Netherlands. a.vink@umcutrecht.nl
Schoneveld
Arjan H
AH
Lamers
Dennis
D
Houben
Anna J S
AJ
van der Groep
Petra
P
van Diest
Paul J
PJ
Pasterkamp
Gerard
G
D000818:Animals; D002340:Carotid Artery Diseases / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D016894:Endarterectomy, Carotid; D005263:Femoral Artery / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D005487:Foam Cells / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D016260:Monocytes, Activated Killer / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010641:Phenotype; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A