4.7 Article

Expression and Roles of Individual HIF Prolyl 4-Hydroxylase Isoenzymes in the Regulation of the Hypoxia Response Pathway along the Murine Gastrointestinal Epithelium

期刊

出版社

MDPI
DOI: 10.3390/ijms22084038

关键词

jejunum; colon; caecum; epithelium; ddPCR; HIF; HIF-prolyl 4-hydroxylase; mRNA

资金

  1. EMBO short-term fellowship
  2. FEBS fellowship
  3. Academy of Finland [296498, 308009]
  4. Sigrid Juselius Foundation
  5. Jane and Aatos Erkko Foundation
  6. Academy of Finland (AKA) [296498, 308009, 296498, 308009] Funding Source: Academy of Finland (AKA)

向作者/读者索取更多资源

HIF prolyl 4-hydroxylases (HIF-P4H) control the powerful mechanism regulating cellular adaptation to decreased oxygenation and the gastrointestinal epithelium has a well-designed control over this adaptation. The gene expression levels of HIF pathway components were found to be higher towards the distal end of the gastrointestinal tract, with HIF-P4H-2 playing a predominant role in the gut epithelium. These findings suggest the development of selective inhibitors targeting specific HIF-P4H isoforms may be useful for diverging therapeutic needs.
The HIF prolyl 4-hydroxylases (HIF-P4H) control hypoxia-inducible factor (HIF), a powerful mechanism regulating cellular adaptation to decreased oxygenation. The gastrointestinal epithelium subsists in physiological hypoxia and should therefore have an especially well-designed control over this adaptation. Thus, we assessed the absolute mRNA expression levels of the HIF pathway components, Hif1a, HIF2a, Hif-p4h-1, 2 and 3 and factor inhibiting HIF (Fih1) in murine jejunum, caecum and colon epithelium using droplet digital PCR. We found a higher expression of all these genes towards the distal end of the gastrointestinal tract. We detected mRNA for Hif-p4h-1, 2 and 3 in all parts of the gastrointestinal tract. Hif-p4h-2 had significantly higher expression levels compared to Hif-p4h-1 and 3 in colon and caecum epithelium. To test the roles each HIF-P4H isoform plays in the gut epithelium, we measured the gene expression of classical HIF target genes in Hif-p4h-1(-/-), Hif-p4h-2 hypomorph and Hif-p4h-3(-/-) mice. Only Hif-p4h-2 hypomorphism led to an upregulation of HIF target genes, confirming a predominant role of HIF-P4H-2. However, the abundance of Hif-p4h-1 and 3 expression in the gastrointestinal epithelium implies that these isoforms may have specific functions as well. Thus, the development of selective inhibitors might be useful for diverging therapeutic needs.

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