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- Title
Survivin Is a Transcriptional Target of STAT3 Critical to Estradiol Neuroprotection in Global Ischemia.
- Authors
Sehara, Yoshihide; Sawicka, Kirsty; Jee-Yeon Hwang; Latuszek-Barrantes, Adrianna; Etgen, Anne M.; Zukin, R. Suzanne
- Abstract
Transient global ischemia causes selective, delayed death of hippocampal CAI pyramidal neurons in humans and animals. It is well established that estrogens ameliorate neuronal death in animal models of focal and global ischemia. However, the role of signal transducer and activator of transcription-3 (STAT3) and its target genes in estradiol neuroprotection in global ischemia remains unclear. Here we show that a single intracerebral injection of 17ß-estradiol to ovariectomized female rats immediately after ischemia rescues CAI neurons destined to die. Ischemia promotes activation of STAT3 signaling, association of STAT3 with the promoters of target genes, and STAT3-dependent mRNA and protein expression of prosurvival proteins in the selectively vulnerable CAI. In animals subjected to ischemia, acute postischemic estradiol further enhances activation and nuclear translocation of STAT3 and STAT3-dependent transcription of target genes. Importantly, we show that STAT3 is critical to estradiol neuroprotection, as evidenced by the ability of STAT3 inhibitor peptide and STAT3 shRNA delivered directly into the CAI of living animals to abolish neuroprotection. In addition, we identify survivin, a member of the inhibitor-of-apoptosis family of proteins and known gene target of STAT3, as essential to estradiol neuroprotection, as evidenced by the ability of shRNA to survivin to reverse neuroprotection. These findings indicate that ischemia and estradiol act synergistically to promote activation of STAT3 and STAT3-dependent transcription of survivin in insulted CAI neurons and identify STAT3 and survivin as potentially important therapeutic targets in an in vivo model of global ischemia.
- Subjects
ISCHEMIA; NEURONS; ANIMAL models in research; LABORATORY rats; THERAPEUTICS
- Publication
Journal of Neuroscience, 2013, Vol 33, Issue 30, p12354
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.1852-13.2013