HIF-1 expression in healing wounds: HIF-1α induction in primary inflammatory cells by TNF-α

Abstract

The expression of the hypoxia-responsive transcription factor hypoxia-inducible factor (HIF)-1 during acute inflammation was investigated in experimental wounds. HIF-1alpha mRNA was maximally expressed in wound cells 6 h after injury. HIF-1alpha protein was detectable in wound cells 1 and 5 days after injury. Cells from 1-day-old wounds were not hypoxic, as determined by lack of pimonidazole hydrochloride adduct formation. Tumor necrosis factor (TNF)-alpha, but not interleukin-1beta, increased the HIF-1alpha protein content of cells isolated 1 and 5 days after injury, and also of glycogen-elicited peritoneal cells, but not HIF-1alpha mRNA. HIF-1alpha did not accumulate in TNF-alpha-treated HeLa, NIH/3T3, NR8383, or RAW 264.7 cells. Nitric oxide from S-nitrosoglutathione did not induce HIF-1alpha accumulation or modulate the response to TNF-alpha. TNF-alpha did not increase oxygen consumption or result in the production of reactive oxygen intermediates by day 1 wound cells. Vascular endothelial growth factor mRNA in wound cells peaked 24 h after wounding. HIF-1 expression in early wounds may contribute to the regulation of inducible nitric oxide synthase and vascular endothelial growth factor, two HIF-1-responsive genes intimately related to the process of repair.

Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification

“…3 E-G). Of note, inflammation is a common feature of both models, and therefore Hif1α stabilization is not an unexpected finding (13).…”

“…1). In our evaluation of HIF1α, we queried the Ingenuity Pathway Knowledgebase for HIF1α downstream genes for which expression levels are previously known to be changed by activation of HIF1α (13,14). The expression level of HIF1α was significantly up-regulated after burns [fold change = 2.103, false-discovery rate (FDR) < 0.05] with pathway activation z-score of 4.965, placing it within the top 50 up-regulated genes.…”

Tumor Necrosis Factor-α Causes Accumulation of a Ubiquitinated Form of Hypoxia Inducible Factor-1α through a Nuclear Factor-κB-Dependent Pathway

“…Furthermore, in primary inflammatory cells, TNF-␣ but not IL-1␤ induced HIF-1␣ protein accumulation. The capacity to enhance HIF-1␣ accumulation was also noticed in inflammatory, TNF-␣-stimulated peritoneal neutrophils but not in a variety of cell lines (Albina et al, 2001). Mechanistically, it has been proposed that oxygen radical formation in response to TNF-␣ facilitates HIF-1␣ accumulation (Haddad and Land, 2001).…”

“…However, details of HIF-1 regulation by TNF-␣ remain unclear, although the involvement of a reactive oxygen species (ROS)-sensitive pathway has been reported (Haddad and Land, 2001). Meanwhile, the role of ROS in stabilizing or destabilizing HIF-1␣ is controversial, and a unifying concept awaits clarification (Albina et al, 2001;Sandau et al, 2001b). However, considering the impact of cytokines during inflammation, one needs to know how cytokines contribute to HIF-1 regulation and whether mechanisms of HIF-1␣ accumulation share components established to operate during hypoxia.…”

The angiogenic response to PLL-g-PEG-mediated HIF-1α plasmid DNA delivery in healthy and diabetic rats

“…Instead of the local administration of expensive protein cocktails, we established and used a system to deliver therapeutic DNA encoding a modified version of the alpha subunit of HIF-1, which escapes normoxic degradation due to the lack of its oxygendependent degradation domain (ODD) [22]. HIF-1 controls the expression of several proteins required for the induction and correct assembly of blood vessels [18] and has been shown to improve wound healing [33,37,38]. Since excessive over-expression of the HIF-1α subunit may correlate with pathophysiological tissue alteration and cancer growth [39], it is essential to temporarily control the expression pattern and to adapt it to the demand of the clinical situation.…”