1. Gastroenterology. 2010 Mar;138(3):1143-54.e1-2. Epub 2009 Oct 8.

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

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 RA, Maxwell P, Baes M, Ratcliffe P,
Carmeliet P.

Department of General, Visceral and Transplantation Surgery, University of
Heidelberg, Germany.

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. Copyright 2010 AGA Institute.
Published by Elsevier Inc. All rights reserved.

PMID: 19818783 [PubMed - indexed for MEDLINE]