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 Harris, Patrick Maxwell, Myriam BaesPeter Ratcliffe, Peter Carmeliet

Research output: Contribution to journalArticle

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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
JournalGastroenterology
Volume138
Issue number3
DOIs
StatePublished - Mar 2010

Fingerprint

Prolyl Hydroxylases
Reperfusion Injury
Ischemia
Liver
Enzymes
Reperfusion
Hepatocytes
RNA Interference
Constriction
Oxygen Consumption
Small Interfering RNA
Skeletal Muscle
Oxidative Stress

Keywords

  • Ischemia/Reperfusion
  • PHD1
  • Prolyl Hydroxylase

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Schneider, M., Van Geyte, K., Fraisl, P., Kiss, J., Aragonés, J., Mazzone, M., ... Carmeliet, P. (2010). Loss or Silencing of the PHD1 Prolyl Hydroxylase Protects Livers of Mice Against Ischemia/Reperfusion Injury. Gastroenterology, 138(3). https://doi.org/10.1053/j.gastro.2009.09.057

Loss or Silencing of the PHD1 Prolyl Hydroxylase Protects Livers of Mice Against Ischemia/Reperfusion Injury. / Schneider, Martin; Van Geyte, Katie; Fraisl, Peter; Kiss, Judit; Aragonés, Julián; Mazzone, Massimiliano; Mairbäurl, Heimo; De Bock, Katrien; Jeoung, Nam Ho; Mollenhauer, Martin; Georgiadou, Maria; Bishop, Tammie; Roncal, Carmen; Sutherland, Andrew; Jordan, Benedicte; Gallez, Bernard; Weitz, Jürgen; Harris, Robert; Maxwell, Patrick; Baes, Myriam; Ratcliffe, Peter; Carmeliet, Peter.

In: Gastroenterology, Vol. 138, No. 3, 03.2010.

Research output: Contribution to journalArticle

Schneider, M, Van Geyte, K, Fraisl, P, Kiss, J, Aragonés, J, Mazzone, M, Mairbäurl, H, De Bock, K, Jeoung, NH, Mollenhauer, M, Georgiadou, M, Bishop, T, Roncal, C, Sutherland, A, Jordan, B, Gallez, B, Weitz, J, Harris, R, Maxwell, P, Baes, M, Ratcliffe, P & Carmeliet, P 2010, 'Loss or Silencing of the PHD1 Prolyl Hydroxylase Protects Livers of Mice Against Ischemia/Reperfusion Injury', Gastroenterology, vol. 138, no. 3. https://doi.org/10.1053/j.gastro.2009.09.057
Schneider, Martin ; Van Geyte, Katie ; Fraisl, Peter ; Kiss, Judit ; Aragonés, Julián ; Mazzone, Massimiliano ; Mairbäurl, Heimo ; De Bock, Katrien ; Jeoung, Nam Ho ; Mollenhauer, Martin ; Georgiadou, Maria ; Bishop, Tammie ; Roncal, Carmen ; Sutherland, Andrew ; Jordan, Benedicte ; Gallez, Bernard ; Weitz, Jürgen ; Harris, Robert ; Maxwell, Patrick ; Baes, Myriam ; Ratcliffe, Peter ; Carmeliet, Peter. / Loss or Silencing of the PHD1 Prolyl Hydroxylase Protects Livers of Mice Against Ischemia/Reperfusion Injury. In: Gastroenterology. 2010 ; Vol. 138, No. 3.
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AU - Schneider, Martin

AU - Van Geyte, Katie

AU - Fraisl, Peter

AU - Kiss, Judit

AU - Aragonés, Julián

AU - Mazzone, Massimiliano

AU - Mairbäurl, Heimo

AU - De Bock, Katrien

AU - Jeoung, Nam Ho

AU - Mollenhauer, Martin

AU - Georgiadou, Maria

AU - Bishop, Tammie

AU - Roncal, Carmen

AU - Sutherland, Andrew

AU - Jordan, Benedicte

AU - Gallez, Bernard

AU - Weitz, Jürgen

AU - Harris, Robert

AU - Maxwell, Patrick

AU - Baes, Myriam

AU - Ratcliffe, Peter

AU - Carmeliet, Peter

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