Schneider, M and Van Geyte, K and Fraisl, P and Kiss, J and Aragones, J and Mazzone, M and Mairbaurl, H and De Bock, K and Jeoung, NH and Mollenhauer, M and Georgiadou, M and Bishop, T and Roncal, C and Sutherland, A and Jordan, B and Gallez, B and Weitz, J and Harris, RA and Maxwell, P and Baes, M and Ratcliffe, P and Carmeliet, P (2010) Loss or Silencing of the PHD1 Prolyl Hydroxylase Protects Livers of Mice Against Ischemia/Reperfusion Injury. GASTROENTEROLOGY , 138 (3) 1143 - U438. 10.1053/j.gastro.2009.09.057.
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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.
|Title:||Loss or Silencing of the PHD1 Prolyl Hydroxylase Protects Livers of Mice Against Ischemia/Reperfusion Injury|
|Keywords:||PHD1, Prolyl Hydroxylase, Ischemia/Reperfusion, ISCHEMIA-REPERFUSION INJURY, RAT HEPATOCYTES, WARM ISCHEMIA, HYPOXIA, TRANSPLANTATION, RESPIRATION, NEUTROPHILS, INHIBITION, ADAPTATION, DEFICIENCY|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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