http://stroke.ahajournals.org/content/early/2012/08/24/STROKEAHA.112.669598.abstract
Abstract
Background and Purpose—Numerous
factors involved in the adaptive response to hypoxia, including
erythropoietin and vascular endothelial growth factor
are transcriptionally regulated by
hypoxia-inducible factors (HIFs). During normoxia, prolyl-4-hydroxylase
domain (PHD) proteins
hydroxylate HIF-α subunits, resulting in
their degradation. We investigated the effect of neuronal deletion of
PHD2, the most
abundant isoform in brain, for stroke
outcome.
Methods—We generated neuron-specific Phd2
knockout mice and subjected animals to systemic hypoxia or transient
middle cerebral artery occlusion. Infarct volume and
cell death were determined by histology.
HIF-1α, HIF-2α, and HIF target genes were analyzed by immunoblotting and
real-time
polymerase chain reaction, respectively.
Results—Neuron-specific ablation of Phd2
significantly increased protein stability of HIF-1α and HIF-2α in the
forebrain and enhanced expression of the neuroprotective
HIF target genes erythropoietin and vascular
endothelial growth factor as well as glucose transporter and
glycolysis-related
enzymes under hypoxic and ischemic
conditions. Mice with Phd2-deficient neurons subjected to
transient cerebral ischemia exhibited a strong reduction in infarct
size, and cell death of
hippocampal CA1 neurons located in the
peri-infarct region was dramatically reduced in these mice. Vessel
density in forebrain
subregions, except for caudate–putamen, was
not altered in Phd2-deficient animals.
Conclusions—Our
findings denote that the endogenous adaptive response on
hypoxic–ischemic insults in the brain is at least partly dependent
on the activity of HIFs and identify PHD2 as
the key regulator for the protective hypoxia response. The results
suggest that
specific inhibition of PHD2 may provide a
useful therapeutic strategy to protect brain tissue from ischemic
injury.
No comments:
Post a Comment