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Neuroprotective effects of HSF1 in retinal ischemia-reperfusion injury

Aryan Pashaei-Marandi

University of Texas Medical Branch


Introduction: Retinal ischemia, a common cause of several vision-threatening diseases, contributes to the death of retinal neurons, particularly retinal ganglion cells (RGCs). Heat shock transcription factor 1 (HSF1). 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 retinal neuronal injury remains uncertain. Our observations suggested the hypothesis that the overexpression of HSF1 in mice using transgenic (Tg) mice carrying the full-length human HSF gene provides neuroprotective effects against retinal IR injury and increasing HSF1 expression could be a beneficial strategy to limit neuronal degeneration in retinal diseases. Methods: Acute retinal ischemia was induced using a standardized retinal ischemia-reperfusion injury protocol. Mice were anesthetized and the anterior chamber of the mouse eye was cannulated with a 30-gauge infusion needle connected to a saline reservoir. Intraocular pressure (IOP) was raised to 110 mm Hg for 45 minutes. Eyes were collected from 12 hours to 7 days after ischemic reperfusion (IR) for further analysis. Transgenic mice carrying full-length human HSF gene were compared to wild-type mice. Each procedure was performed with a corresponding sham control in the left eye. HSF1 expression was measured by IHC. RGCs were counted in retinal flat mount after staining with Tuj-1. ER stress-related molecules are measured by immunohistochemistry. Apoptosis following IR was measured using the TUNEL assay to detect apoptotic DNA fragmentation differences between the WT-control and the HSF1 Tg mice after 24h hours. Comparisons were analyzed by Student’s t-test or one-way ANOVA followed by Newman Keuls post hoc test. A p-value < 0.05 was considered statistically significant. Results: HSF1 expression increased in ischemic reperfusion. Immunostaining with HSF1 antibody showed evidence of HSF1 overexpression in WT mice under ischemic stress and HSF1 Tg control mice. n=3 for WT-IR (p<.05 versus WT-IR). N=3 for HSF1-Tg control. (p<.01 versus WT-control). The overexpression of HSF1 in Tg mice prevented ganglion cell complex thinning (GCC) and death after IR; n=6. (p<0.05 versus Tg control)(p<0.05 versus WT IR). The GCC is defined as the summation of the area of the thickness of the retinal nuclear fiber layer, the retinal ganglion cell layer, and the inner plexiform layer. HSF1 overexpression decr

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