Sun Yu, George Jacob, Rocha Sonia
Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, United Kingdom.
Division of Medical Sciences, Ninewells Hospital and Medical School, Dundee, United Kingdom.
PLoS One. 2015 Apr 1;10(4):e0123649. doi: 10.1371/journal.pone.0123649. eCollection 2015.
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.
别嘌醇是一种黄嘌呤氧化酶抑制剂，已用于心血管疾病和慢性肾病患者的临床试验。这两种疾病与缺氧以及转录因子缺氧诱导因子（HIF）家族的激活有着广泛的联系。在此，我们分析了别嘌醇治疗在两种不同细胞模型中的效果及其对缺氧的反应。我们探究了别嘌醇在缺氧和常氧条件下对人包皮成纤维细胞（HFF）和人脐静脉内皮细胞（HUVEC）的剂量依赖性作用。在常氧和缺氧条件下，高剂量别嘌醇均可降低HFF和HUVEC细胞中HIF-1α蛋白的积累。别嘌醇对这两种细胞体系中HIF-1α mRNA水平的影响甚微。有趣的是，别嘌醇对HIF系统的作用与脯氨酰羟化酶活性无关。最后，在体外模型中，别嘌醇治疗降低了HUVEC细胞的血管生成特性。综上所述，这些结果表明高剂量别嘌醇可抑制细胞中的HIF系统和促血管生成特性。
