Loss or silencing of the PHD1 prolyl hydroxylase protects livers of mice against ischemia/reperfusion injury.
OBJECTIVE
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.
Schneider
Martin
M
Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Germany.
Van Geyte
Katie
K
Fraisl
Peter
P
Kiss
Judit
J
Aragonés
Julián
J
Mazzone
Massimiliano
M
Mairbäurl
Heimo
H
De Bock
Katrien
K
Jeoung
Nam Ho
NH
Mollenhauer
Martin
M
Georgiadou
Maria
M
Bishop
Tammie
T
Roncal
Carmen
C
Sutherland
Andrew
A
Jordan
Benedicte
B
Gallez
Bernard
B
Weitz
Jürgen
J
Harris
Robert A
RA
Maxwell
Patrick
P
Baes
Myriam
M
Ratcliffe
Peter
P
Carmeliet
Peter
P
D000222:Adaptation, Physiological; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D022781:Hepatocytes / Q000201:enzymology* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008107:Liver Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D010101:Oxygen Consumption; D011393:Procollagen-Proline Dioxygenase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015427:Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011393:Procollagen-Proline Dioxygenase; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C522721:PHD1 protein, mouse