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 Ho Jeoung, Nam Mollenhauer, Martin Georgiadou, Maria Bishop, Tammie Roncal, Carmen [KUL] Sutherland, Andrew Jordan, Bénédicte [UCL] Gallez, Bernard [UCL] Weitz, Jürgen Harris, Robert A. Maxwell, Patrick Baes, Myriam Ratcliffe, Peter Carmeliet, Peter et al.[show all]

BACKGROUND & AIMS:: Liver ischemia/reperfusion (I/R) injury is a frequent cause of organ dysfunction. Loss of the oxygen sensor 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 min later, livers were reperfused for 8 h for I/R experiments. Hepatocyte damage following ischemia or I/R was investigated in PHD1-deficient (PHD1-/-) and wild-type (WT) mice or following shRNA-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 non-ischemic liver lobes, more than half of the WT mice succumbed whereas all PHD1-/- mice survived. Also, short-term inhibition of PHD1 via RNAi-mediated silencing provided protection against I/R. Knockdown of PHD1 also induced hypoxia tolerance of hepatocytes in vitro. Mechanistically, loss of PHD1 decreased the production of oxidative stress, which likely relates to a decrease in oxygen consumption, as a result of a reprogramming of hepatocellular metabolism. CONCLUSION:: 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.