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HIF-1alpha expression is associated with an atheromatous inflammatory plaque phenotype and upregulated in activated macrophages

      Abstract

      Objective

      Angiogenesis and inflammation are important features in atherosclerotic plaque destabilization. The transcription factor hypoxia-inducible factor-1 alpha (HIF-1α) is a key regulator of angiogenesis and is also involved in inflammatory reactions. We studied HIF-1α expression in different atherosclerotic plaque phenotypes.

      Methods and results

      HIF-1α expression was observed in 18/37 (49%) carotid and in 9/15 (60%) femoral endarterectomy specimens. Expression of HIF-1α was associated with the presence of a large extracellular lipid core (P = 0.03) and macrophages (P = 0.02). HIF-1α co-localized with vascular endothelial growth factor (VEGF), an important downstream target of HIF-1α. In addition, a strong association was observed between expression levels of HIF-1α and VEGF (P = 0.001). The average number of plaque microvessels was higher in plaques with no or minor HIF-1α staining than in plaques with moderate or heavy HIF-1α staining (P = 0.03). In human macrophages, lipopolysaccharide activation induced HIF-1α expression. In embryonic fibroblasts derived from wild-type mice, lipopolysaccharide activation induced an increase in HIF-1α 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-1α is associated with an atheromatous inflammatory plaque phenotype and with VEGF expression. HIF-1α expression is upregulated in activated macrophages under normoxic conditions.

      Keywords

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