Loss or Silencing of the PHD1 Prolyl Hydroxylase Protects Livers of Mice Against Ischemia/Reperfusion Injury

Martin Schneider, Katie Van Geyte, Peter Fraisl, Judit Kiss, Julián Aragonés, Massimiliano Mazzone, Heimo Mairbäurl, Katrien De Bock, Nam Ho Jeoung, Martin Mollenhauer, Maria Georgiadou, Tammie Bishop, Carmen Roncal, Andrew Sutherland, Benedicte Jordan, Bernard Gallez, Jürgen Weitz, Robert A. Harris, Patrick Maxwell, Myriam BaesPeter Ratcliffe, Peter Carmeliet

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

Background & Aims: Liver ischemia/reperfusion (I/R) injury is a frequent cause of organ dysfunction. Loss of the oxygen sensor prolyl hydroxylase domain enzyme 1 (PHD1) causes tolerance of skeletal muscle to hypoxia. We assessed whether loss or short-term silencing of PHD1 could likewise induce hypoxia tolerance in hepatocytes and protect them against hepatic I/R damage. Methods: Hepatic ischemia was induced in mice by clamping of the portal vessels of the left lateral liver lobe; 90 minutes later livers were reperfused for 8 hours for I/R experiments. Hepatocyte damage following ischemia or I/R was investigated in PHD1-deficient (PHD1-/-) and wild-type mice or following short hairpin RNA-mediated short-term inhibition of PHD1 in vivo. Results: PHD1-/- livers were largely protected against acute ischemia or I/R injury. Among mice subjected to hepatic I/R followed by surgical resection of all nonischemic liver lobes, more than half of wild-type mice succumbed, whereas all PHD1-/- mice survived. Also, short-term inhibition of PHD1 through RNA interference-mediated silencing provided protection against I/R. Knockdown of PHD1 also induced hypoxia tolerance of hepatocytes in vitro. Mechanistically, loss of PHD1 decreased production of oxidative stress, which likely relates to a decrease in oxygen consumption as a result of a reprogramming of hepatocellular metabolism. Conclusions: Loss of PHD1 provided tolerance of hepatocytes to acute hypoxia and protected them against I/R-damage. Short-term inhibition of PHD1 is a novel therapeutic approach to reducing or preventing I/R-induced liver injury.

Original languageEnglish (US)
Pages (from-to)1143-1154.e2
JournalGastroenterology
Volume138
Issue number3
DOIs
StatePublished - Mar 2010

Keywords

  • Ischemia/Reperfusion
  • PHD1
  • Prolyl Hydroxylase

ASJC Scopus subject areas

  • Gastroenterology

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    Schneider, M., Van Geyte, K., Fraisl, P., Kiss, J., Aragonés, J., Mazzone, M., Mairbäurl, H., De Bock, K., Jeoung, N. H., Mollenhauer, M., Georgiadou, M., Bishop, T., Roncal, C., Sutherland, A., Jordan, B., Gallez, B., Weitz, J., Harris, R. A., Maxwell, P., ... Carmeliet, P. (2010). Loss or Silencing of the PHD1 Prolyl Hydroxylase Protects Livers of Mice Against Ischemia/Reperfusion Injury. Gastroenterology, 138(3), 1143-1154.e2. https://doi.org/10.1053/j.gastro.2009.09.057