Department of Ophthalmology & Visual Sciences, University of Texas Medical Branch, Galveston, Texas, United States.
Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Invest Ophthalmol Vis Sci. 2019 Mar 1;60(4):965-977. doi: 10.1167/iovs.18-26216.
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), 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).
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 endoplasmic reticulum (ER) stress branches, tau phosphorylation, inflammatory molecules, and RGC injury were determined by immunohistochemistry, Western blot, or quantitative PCR.
HSF1 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.
These 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.
视网膜缺血是多种威胁视力疾病的常见病因，可导致视网膜神经元死亡，尤其是视网膜神经节细胞（RGCs）。热休克转录因子 1（HSF1）是一种应激反应蛋白，在应对包括缺血在内的细胞应激刺激方面具有重要作用。本研究旨在探讨 HSF1 在视网膜缺血再灌注（IR）小鼠模型中是否对视网膜神经元损伤起作用。
通过将灌注针插入右眼前房并将连接到针上的盐水储液器升高，将眼内压升高至 110mmHg 持续 45 分钟，从而诱导 IR。通过免疫组织化学、Western blot 或定量 PCR 测定 HSF1、Hsp70、内质网（ER）应激分支中的分子、tau 磷酸化、炎症分子和 RGC 损伤。
IR 后 6 小时，视网膜中 HSF1 的表达显著增加。使用我们携带全长人 HSF 基因的新型转基因小鼠，我们证明 IR 诱导的视网膜神经元凋亡和坏死在 IR 后 12 小时被消除。在 IR 后 7 天，HSF1 转基因小鼠的 RGC 及其功能得以保留。从机制上讲，HSF1 的有益作用可能是通过诱导伴侣蛋白 Hsp70 和减轻 ER 应激来介导的，导致 tau 磷酸化减少和炎症反应减弱，在 IR 后 12 至 24 小时。
这些数据提供了令人信服的证据，表明 HSF1 对视网膜 IR 损伤具有神经保护作用，增强 HSF1 表达可能是限制视网膜疾病中神经元变性的有益策略。
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