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Int6 silencing causes induction of angiogenic factors in neuronal cells via accumulation of hypoxia-inducible factor 2alpha and decreases brain damage in rats.

Authors: Miyashita, R  Chen, L  Oshiro, H  Uchino, H  Shibasaki, F 
Citation: Miyashita R, etal., Neurosci Lett. 2012 Oct 18;528(1):83-8. doi: 10.1016/j.neulet.2012.08.033. Epub 2012 Aug 28.
Pubmed: (View Article at PubMed) PMID:22960363
DOI: Full-text: DOI:10.1016/j.neulet.2012.08.033

We have previously shown that when siRNA against Int6 (siRNA-Int6) was used, hypoxia-inducible factor 2alpha (HIF2alpha) activity was stabilized even under normoxic conditions, and the expression of several angiogenic factors was increased. In neuronal tissues, the mechanism underlying angiogenesis remains largely unknown. In the current study, we investigate the role of the tumor suppressor Int6/eIF3e in the regulation of the expression of angiogenic factors in neuronal cells. In addition, we test whether siRNA-Int6 reduces cold-induced brain damage in rats. We used human neuroblastoma SHSY5Y cells transfected with either siRNA-Int6, or a negative control siRNA. Real-time PCR and supersensitive multiplex assay were used to detect gene and protein expression of several angiogenic factors after transfection. For the animal studies, Wistar rats were subjected to brain damage by cold injury, and 50 mug siRNA-Int6, 100 mug siRNA-Int6, or negative control was administrated. At day 7 post-treatment, brain sections were stained and image analysis system was used to determine the damaged area. Our experiments using SHSY5Y cells revealed a significant effect of siRNA-Int6 on the expression of HIF2alpha but not HIF1alpha, both at 8 and 24h after transfection. The siRNA-Int6 led to significant up-regulation of angiogenic factors, including vascular endothelial growth factor and platelet-derived growth factor-B, both at the mRNA and protein levels. Furthermore, our animal studies revealed significantly reduced area of cold-induced damage in rats receiving siRNA-Int6, compared to negative controls. Our findings indicate that Int6 act as a hypoxia-independent master switch of angiogenesis in neuronal cells, and that inhibition of Int6 by siRNA may be an effective therapeutic strategy in treating ischemic diseases such as brain ischemia and injury.


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RGD ID: 10395371
Created: 2015-09-03
Species: All species
Last Modified: 2015-09-03
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.