Role for HIF-1α and Downstream Pathways in Regulating Neuronal Injury after Intracerebral Hemorrhage in Diabetes.
OBJECTIVE
HIF-1α is accumulated in the cellular nucleus and cytoplasm under conditions of oxygen deprivation and engaged in pathophysiologic changes of homeostasis by modulating the expression of several target genes. As an endogenous signaling protein, HIF-1α contributes to in neuroprotection, erythropoiesis, and apoptosis modulation. The purpose of this study was to examine the role played by HIF-1α in regulating neurological injury evoked by intracerebral hemorrhage (ICH) through its downstream product, namely vascular endothelial growth factor (VEGF). In particular, we examined the effects of diabetic hyperglycemia on HIF-1α response in the processing of ICH.


METHODS
ELISA was used to measure HIF-1α and VEGF; and Western Blot analysis to examine the protein expression of VEGFR-2 and Caspase-3. Neurological Severity Score and brain water content were used to indicate neurological function and brain edema.


RESULTS
HIF-1α and VEGF were significantly increased in the brain after induction of ICH in non-diabetic control rats and diabetic rats; however, the amplified levels of HIF-1α and VEGF were attenuated in diabetic rats (P<0.05 vs. non-diabetic rats) as compared with non-diabetic rats. Also, the protein expression of VEGF receptor subtype 2 was significantly less in the brain of diabetic rats (P<0.05 vs. non-diabetic rats). Further, cerebral infusion of HIF-1 activator stabilized VEGF levels, attenuated Caspase-3 and improved neurological deficits induced by ICH and the effects are smaller in diabetic animals.


CONCLUSIONS
HIF-1α activated by ICH likely plays a beneficial role via VEGF mechanisms and response of HIF-1α is largely impaired in diabetes. This has pharmacological implications to target specific HIF-1α and VEGF pathway for neuronal dysfunction and vulnerability related to ICH.
Department of Neurology, Chongqing University of Medical Sciences, the Second Affiliated Hospital, Chongqing, China.
Zhen
Z
Yu
Ling
L
Tang
Lifen
L
Chen
Jinfang
J
Li
Wanfu
W
Wu
Changlin
C
Hu
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000378:metabolism; D001929:Brain Edema / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002543:Cerebral Hemorrhage / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D053148:Caspase 3