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

Aryan Vink, Arjan H. Schoneveld, Dennis Lamers, Anna J S Houben, Petra van der Groep, Paul J. van Diest, Gerard Pasterkamp

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
JournalAtherosclerosis
Volume195
Issue number2
DOIs
StatePublished - Dec 2007
Externally publishedYes

Keywords

  • Angiogenesis
  • Atherosclerosis
  • Hypoxia
  • Immune system
  • Inflammation
  • LPS
  • Macrophage
  • Microvessel
  • Neovascularization
  • Peripheral artery disease
  • Peripheral vascular disease
  • TLR4
  • Toll-like receptor
  • Vascular endothelial growth factor
  • Vulnerable plaque

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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