Loss or silencing of the PHD1 prolyl hydroxylase protects livers of mice against ischemia/reperfusion injury

M Schneider, K Van Geyte, P Fraisl, J Kiss, J Aragonés… - Gastroenterology, 2010 - Elsevier
M Schneider, K Van Geyte, P Fraisl, J Kiss, J Aragonés, M Mazzone, H Mairbäurl, K De Bock
Gastroenterology, 2010Elsevier
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 …
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.
Elsevier