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FAN XIA, Wei Liu, Yonju Ha, Shuang Zhu, Yi Li, Oluwarotimi Folorunso, Aryan Pashaei-Marandi, Pei Yi LIN, Ronald G Tilton, Anson P Pierce, Hua Liu, Wenbo Zhang; Overexpressing HSF1 prevents retinal neuronal injury in ischemic retinopathy. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1633. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Heat shock transcription factor 1 (HSF1), a stress-responsive protein, has been shown to be important in response to cellular stress stimuli, including ischemia. However, its specific role in ischemic retinopathy remains unknown. In this study, we studied the role of HSF1 in retinal neuronal damage after ischemic injury in vivo.
Studies were performed on wild-type (WT) mice and HSF1 transgenic mice carrying full-length human HSF1 gene. Retinal ischemia-reperfusion (IR) was induced by inserting an infusion needle into the anterior chamber of the right eye and elevating a saline reservoir connected to the needle to raise the intraocular pressure to 110 mm Hg for 45 minutes. HSF1, HSP70, molecules in the ER stress branches, tau phosphorylation, inflammatory molecules and retinal ganglion cell (RGC) injury were determined by immunohistochemistry, Western blot or quantitative PCR. Dark-adapted electroretinography (ERG) analysis was performed to determine the function of RGCs after IR.
HSF1 was primarily localized in retinal ganglion cell and inner nuclear layers. Its mRNA and protein expressions were significantly increased in the retina at 6 hours and 12 hours after IR injury (mRNA: 182.6 ± 20.7 % & 146.6 ± 18.6%; protein: 301.5 ± 40.5 % & 221.2 ± 48.2 % of non-injured retina, n=4, p<0.05), followed by a return to normal level at 24 hours after injury. Overexpression of HSF1 significantly induced chaperone protein Hsp70, alleviated endoplasmic-reticulum (ER) stress, leading to decreased tau aggregation and attenuated inflammatory response at 12 hours after IR injury. Furthermore, at 12 hours after IR, TUNEL and PI uptake assays demonstrated that retinal neuronal apoptosis and necroptosis were significantly abrogated by 79.6 % (n=4, p<0.05) and 63.6 % (n=6, p<0.05) in HSF1 transgenic mice. As a result, loss of RGCs was dramatically decreased by 46.4 % (n=6-7, p<0.05), and their function was preserved in HSF1 transgenic mice.
HSF1 is neuroprotective against retinal IR injury and boosting HSF1 expression could be a beneficial strategy to limit neuronal degeneration in retinal diseases.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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