Neuroprotective Effects of HSF1 in Retinal Ischemia-Reperfusion Injury.

Wei Liu,Fan Xia,Oluwarotimi Folorunso,Aryan Pashaei-Marandi,Pei-Yi Lin,Yi Li,Wenbo Zhang,Shuang Zhu,Anson P Pierce,Yonju Ha,Hua Liu,Ronald G Tilton

doi:10.1167/iovs.18-26216

Abstract

PurposeRetinal 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), a stress-responsive protein, has been shown to be important in response to cellular stress stimuli, including ischemia. This study is to investigate whether HSF1 has a role in retinal neuronal injury in a mouse model of retinal ischemia-reperfusion (IR).MethodsIR 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 endoplasmic reticulum (ER) stress branches, tau phosphorylation, inflammatory molecules, and RGC injury were determined by immunohistochemistry, Western blot, or quantitative PCR.ResultsHSF1 expression was significantly increased in the retina 6 hours after IR. Using our novel transgenic mice carrying full-length human HSF gene, we demonstrated that IR-induced retinal neuronal apoptosis and necroptosis were abrogated 12 hours after IR. RGCs and their function were preserved in the HSF1 transgenic mice 7 days after IR. Mechanistically, the beneficial effects of HSF1 may be mediated by its induction of chaperone protein Hsp70 and alleviation of ER stress, leading to decreased tau phosphorylation and attenuated inflammatory response 12 to 24 hours after IR.ConclusionsThese data provide compelling evidence that HSF1 is neuroprotective against retinal IR injury, and boosting HSF1 expression may be a beneficial strategy to limit neuronal degeneration in retinal diseases.

Highlights

MethodsIR 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
Retinal ischemia, a common cause of several vision-threatening diseases, contributes to the death of retinal neurons, retinal ganglion cells (RGCs)
It is a common cause of visual impairment and blindness in various forms of ischemic retinopathy including central retinal artery occlusion, retinal vein occlusion, glaucoma, traumatic optic neuropathy (TON), and diabetic retinopathy.[1,2]

Summary

Methods

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, Hsp[70], molecules in the endoplasmic reticulum (ER) stress branches, tau phosphorylation, inflammatory molecules, and RGC injury were determined by immunohistochemistry, Western blot, or quantitative PCR. Animal protocols were approved by the Institutional Animal Care and Use Committee of the University of Texas Medical Branch. All experimental procedures and use of animals were performed in accordance with the Association for Research in Vision and Ophthalmology Statement for the Use of Animals in Ophthalmic and Vision Research. Mice were maintained on a 12:12 light/dark cycle with food and water available ad libitum.

Results

Discussion

Conclusion