Suppression of hypoxia-inducible factor-1alpha and its downstream genes reduces acute hyperglycemia-enhanced hemorrhagic transformation in a rat model of cerebral ischemia.
We evaluated a role of hypoxia-inducible factor-1alpha (HIF-1alpha) and its downstream genes in acute hyperglycemia-induced hemorrhagic transformation in a rat model of focal cerebral ischemia. Male Sprague-Dawley rats weighing 280-300 g (n = 105) were divided into sham, 90 min middle cerebral artery occlusion (MCAO), MCAO plus HIF-1alpha inhibitors, 2-methoxyestradiol (2ME2) or 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), groups. Rats received an injection of 50% dextrose (6 ml/kg intraperitoneally) at 15 min before MCAO. HIF-1alpha inhibitors were administered at the onset of reperfusion. The animals were examined for neurological deficits and sacrificed at 6, 12, 24, and 72 hr following MCAO. The cerebral tissues were collected for histology, zymography, and Western blot analysis. The expression of HIF-1alpha was increased in ischemic brain tissues after MCAO and reduced by HIF-1alpha inhibitors. In addition, 2ME2 reduced the expression of vascular endothelial growth factor (VEGF) and the elevation of active matrix metalloproteinase-2 and -9 (MMP-2/MMP-9) in the ipsilateral hemisphere. Both 2ME2 and YC-1 reduced infarct volume and ameliorated neurological deficits. However, only 2ME2 attenuated hemorrhagic transformation in the ischemic territory. In conclusion, the inhibition of HIF-1alpha and its downstream genes attenuates hemorrhagic conversion of cerebral infarction and ameliorates neurological deficits after focal cerebral ischemia.
Department of Physiology and Pharmacology, Loma Linda University, 11041 Campus Street, Risley Hall Room 219, Loma Linda, CA 92354, USA.
Chunhua
C
Chen
Robert P
RP
Ostrowski
Changman
C
Zhou
Jiping
J
Tang
John H
JH
Zhang
D000077584:2-Methoxyestradiol; D000208:Acute Disease; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D002491:Central Nervous System Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D006943:Hyperglycemia / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007191:Indazoles / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D020300:Intracranial Hemorrhages / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D002491:Central Nervous System Agents; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007191:Indazoles; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D004958:Estradiol; D000077584:2-Methoxyestradiol