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Selective inhibition of early--but not late--expressed HIF-1α is neuroprotective in rats after focal ischemic brain damage.

ABSTRACT: The expression of hypoxia-inducible factor-1-alpha (HIF-1α) is upregulated in ischemic stroke, but its function is still unclear. In the present study, biphasic expression of HIF-1α was observed during 1-12 h and after 48 h in neurons exposed to ischemic stress in vitro and in vivo. Treating neurons with 2-methoxyestradiol (2ME2) 0.5 h after ischemic stress or pre-silencing HIF-1α with small interfering RNA (siRNA) decreased brain injury, brain edema and number of apoptotic cell, and downregulates Nip-like protein X (Nix) expression. Conversely, applying 2ME2 to neurons 8 h after ischemic stress or silencing the HIF-1α with siRNA 12 h after oxygen-glucose deprivation (OGD) increased neuron damage and decreased vascular endothelial growth factor (VEGF) expression. Taken together, these results demonstrate that HIF-1α induced by ischemia in early and late times leads cellular apoptosis and survival, respectively, and provides a new insight into the divergent roles of HIF-1α expression in neurons after ischemic stroke.

SUBMITTER: Yeh SH

PROVIDER: S-EPMC8094320 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Selective inhibition of early--but not late--expressed HIF-1α is neuroprotective in rats after focal ischemic brain damage.

Yeh Shiu-Hwa SH Ou Li-Chin LC Gean Po-Wu PW Hung Jan-Jong JJ Chang Wen-Chang WC

Brain pathology (Zurich, Switzerland) 20101103 3

The expression of hypoxia-inducible factor-1-alpha (HIF-1α) is upregulated in ischemic stroke, but its function is still unclear. In the present study, biphasic expression of HIF-1α was observed during 1-12 h and after 48 h in neurons exposed to ischemic stress in vitro and in vivo. Treating neurons with 2-methoxyestradiol (2ME2) 0.5 h after ischemic stress or pre-silencing HIF-1α with small interfering RNA (siRNA) decreased brain injury, brain edema and number of apoptotic cell, and downregulat ...[more]

PMID: 21029239

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Project description:Background. Women account for 60% of all stroke deaths and are more often permanently disabled than men, despite their higher observed stroke incidence. Considering the clinical population affected by stroke, an obvious drawback is that many pre-clinical and clinical studies only investigate young males. To improve therapeutic translation from bench to bedside, we believe that it is advantageous to include both sexes in experimental models of stroke. The aims of this study were to identify early cerebral vascular responses to ischemic stroke in females, compare the differential gene expression patterns with those seen in males, and identify potential new therapeutic targets. Results. Transient middle cerebral artery occlusion (tMCAO) was used to induce stroke in both female and male rats, the middle cerebral arteries (MCAs) were isolated 3 hours post reperfusion and RNA was extracted. Affymetrix whole transcriptome expression profiling was performed on female (n = 12) MCAs to reveal differentially expressed genes. In total, 1076 genes had an increased expression and 879 genes a decreased expression in the occluded MCAs as compared with the control MCAs from female rats. An enrichment of genes related to apoptosis, regulation of transcription, protein autophosphorylation, inflammation, oxidative stress, and tissue repair and recovery were seen in the occluded MCA. The high expression genes chosen for qPCR verification (Adamts4, Olr1, JunB, Fosl1, Serpine1, S1pr3, Ccl2 and Socs3) were all shown to be upregulated in the same manner in both females and males after tMCAO (p < 0.05; n = 23). When comparing the differentially expressed genes in female MCAs (occluded and non-occluded) with our previous findings in males after tMCAO, a total of 297 genes overlapped (all groups had 32 genes in common). Conclusions. The cascades of processes initiated in the vasculature following reperfusion are complex. Dynamic gene expression alterations were observed in the occluded MCAs, and to a less pronounced degree in the non-occluded MCAs. Dysregulation of inflammation and blood-brain barrier breakdown are possible pharmacological targets. The sample of genes (<1% of differentially expressed genes) validated for this microarray did not reveal any sex differences.

Dataset Information

Selective inhibition of early--but not late--expressed HIF-1α is neuroprotective in rats after focal ischemic brain damage.

Publications

Selective inhibition of early--but not late--expressed HIF-1α is neuroprotective in rats after focal ischemic brain damage.

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