Repetitive hypoxic preconditioning (HP) enforces protective effects to subsequently severe hypoxic/ischemic stress. We hypothesized that HP may provide protection against
ischemia/reperfusion (I/R) injury in rat livers via
hypoxia-induced factor-1 alpha (HIF-1α)/
reactive oxygen species (ROS)-dependent defensive mechanisms. Female Wistar rats were exposed to
hypoxia (15 h/day) in a hypobaric hypoxic chamber (5500 m) for HP induction, whereas the others were kept in sea level. These rats were subjected to 45 min of hepatic
ischemia by portal vein occlusion followed by 6 h of reperfusion. We evaluated HIF-1α in nuclear extracts, MnSOD, CuZnSOD,
catalase, Bad/Bcl-xL/
caspase 3/
poly-(ADP-ribose)-polymerase (PARP), mitochondrial Bcl-xL, and cytosolic
cytochrome C expression with Western blot and
nitroblue tetrazolium/3-
nitrotyrosine stain. Kupffer cell infiltration and
terminal deoxynucleotidyl transferase-mediated nick-end labeling method apoptosis were determined by immunocytochemistry. The ROS value from liver surface and bile was detected by an ultrasensitive chemiluminescence-amplification method. Hepatic function was assessed with plasma
alanine aminotransferase (ALT) and
aspartate aminotransferase (AST) levels. HP increased nuclear translocation of HIF-1α and enhanced Bcl-xL, MnSOD, CuZnSOD, and
catalase protein expression in a time-dependent manner. The response of HP enhanced hepatic HIF-1α, and Bcl-xL expression was abrogated by a HIF-1α inhibitor YC-1. Hepatic I/R increased ROS levels,
myeloperoxidase activity, Kupffer cell infiltration, ALT and AST levels associated with the enhancement of cytosolic Bad translocation to mitochondria, release of
cytochrome C to cytosol, and activation of
caspase 3/PARP-mediated apoptosis. HP significantly ameliorated hepatic I/R-enhanced oxidative stress, apoptosis, and mitochondrial and hepatic dysfunction. In summary, HP enhances HIF-1α/ROS-dependent cascades to upregulate mitochondrial
Bcl-xL protein expression and to confer protection against I/R injury in the livers.