Abstract
Allopurinol, an inhibitor of xanthine oxidase, has been used in clinical trials of patients with cardiovascular and chronic kidney disease. These are two pathologies with extensive links to hypoxia and activation of the transcription factor hypoxia inducible factor (HIF) family. Here we analysed the effects of allopurinol treatment in two different cellular models, and their response to hypoxia. We explored the dose-dependent effect of allopurinol on Human Foreskin Fibroblasts (HFF) and Human Umbilical Vein Endothelial Cells (HUVEC) under hypoxia and normoxia. Under normoxia and hypoxia, high dose allopurinol reduced the accumulation of HIF-1α protein in HFF and HUVEC cells. Allopurinol had only marginal effects on HIF-1α mRNA level in both cellular systems. Interestingly, allopurinol effects over the HIF system were independent of prolyl-hydroxylase activity. Finally, allopurinol treatment reduced angiogenesis traits in HUVEC cells in an in vitro model. Taken together these results indicate that high doses of allopurinol inhibits the HIF system and pro-angiogenic traits in cells.
Highlights
Allopurinol is an inhibitor of xanthine oxidase (XO) that has been in clinical use for the treatment of gout for over 50 years [1]
To understand how two different cellular systems respond to hypoxia we performed a time course analysis for protein expression of hypoxia inducible factor (HIF) subunits and a selection of its targets in Human Foreskin Fibroblasts (HFF) and Human Umbilical Vein Endothelial Cells (HUVEC) in hypoxia
Both HFF and HUVEC responded to hypoxia by inducing HIF-1α protein levels (Fig 1A)
Summary
Allopurinol is an inhibitor of xanthine oxidase (XO) that has been in clinical use for the treatment of gout for over 50 years [1]. XO is an enzyme responsible for the successive oxidation of hypoxanthine and xanthine, resulting in the production of uric acid, the end-product of the purine catabolic pathway. A by-product of XO action in these reactions is the generation of reactive oxygen species (ROS) such as superoxide anion (O2-) and Hydrogen Peroxide (H2O2) from molecular oxygen [2, 3]. The inhibition of XO by allopurinol has been hypothesised as a possible “oxygen-sparing” mechanism, which may be beneficial in patients with chronic hypoxia [4]. In addition to blocking uric acid production, inhibition of XO leads to an increase in hypoxanthine and xanthine. While xanthine cannot be converted to purines, PLOS ONE | DOI:10.1371/journal.pone.0123649. While xanthine cannot be converted to purines, PLOS ONE | DOI:10.1371/journal.pone.0123649 April 1, 2015
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