Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing, China.
Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing, China; Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China; Beijing Key Laboratory of Fundamental Research on Biomechanics in Clinical Application, Capital Medical University, Beijing, China.
Mol Cell Proteomics. 2023 Nov;22(11):100654. doi: 10.1016/j.mcpro.2023.100654. Epub 2023 Oct 2.
The pathogenesis of glaucoma is still unknown. There are few studies on the dynamic change of tissue-specific and time-specific molecular pathophysiology caused by ocular hypertension (OHT). This study aimed to identify the early proteomic alterations in the retina, optic nerve head (ONH), and optic nerve (ON). After establishing a rat model of OHT, we harvested the tissues from control and glaucomatous eyes and analyzed the changes in protein expression using a multiplexed quantitative proteomics approach (TMT-MS3). Our study identified 6403 proteins after 1-day OHT and 4399 proteins after 7-days OHT in the retina, 5493 proteins after 1-day OHT and 4544 proteins after 7-days OHT in ONH, and 5455 proteins after 1-day OHT and 3835 proteins after 7-days OHT in the ON. Of these, 560 and 489 differential proteins were identified on day 1 and 7 after OHT in the retina, 428 and 761 differential proteins were identified on day 1 and 7 after OHT in the ONH, and 257 and 205 differential proteins on days 1 and 7 after OHT in the ON. Computational analysis on day 1 and 7 of OHT revealed that alpha-2 macroglobulin was upregulated across two time points and three tissues stably. The differentially expressed proteins between day 1 and 7 after OHT in the retina, ONH, and ON were associated with glutathione metabolism, mitochondrial dysfunction/oxidative phosphorylation, oxidative stress, microtubule, and crystallin. And the most significant change in retina are crystallins. We validated this proteomic result with the Western blot of crystallin proteins and found that upregulated on day 1 but recovered on day 7 after OHT, which are promising as therapeutic targets. These findings provide insights into the time- and region-order mechanisms that are specifically affected in the retina, ONH, and ON in response to elevated IOP during the early stages.
青光眼的发病机制尚不清楚。关于眼高压（OHT）引起的组织特异性和时间特异性分子病理生理学的动态变化研究较少。本研究旨在鉴定 OHT 后视网膜、视神经头（ONH）和视神经（ON）中早期蛋白质组学的改变。在建立大鼠 OHT 模型后，我们从对照眼和青光眼眼中采集组织，并使用多重定量蛋白质组学方法（TMT-MS3）分析蛋白质表达的变化。我们的研究在 1 天 OHT 后鉴定了视网膜中的 6403 种蛋白质，在 7 天 OHT 后鉴定了 4399 种蛋白质；在 1 天 OHT 后鉴定了视神经头中的 5493 种蛋白质，在 7 天 OHT 后鉴定了 4544 种蛋白质；在 1 天 OHT 后鉴定了视神经中的 5455 种蛋白质，在 7 天 OHT 后鉴定了 3835 种蛋白质。其中，在 OHT 后第 1 天和第 7 天在视网膜中鉴定了 560 种和 489 种差异蛋白，在 ONH 中鉴定了 428 种和 761 种差异蛋白，在 ON 中鉴定了 257 种和 205 种差异蛋白。OHT 后第 1 天和第 7 天的计算分析显示，α-2 巨球蛋白在两个时间点和三个组织中稳定地上调。OHT 后第 1 天和第 7 天在视网膜、ONH 和 ON 之间的差异表达蛋白与谷胱甘肽代谢、线粒体功能障碍/氧化磷酸化、氧化应激、微管和晶体蛋白有关。在视网膜中最显著的变化是晶体蛋白。我们用晶体蛋白的 Western blot 验证了这个蛋白质组学结果，发现它们在 OHT 后第 1 天上调，但在第 7 天恢复，这是有希望的治疗靶点。这些发现为在早期升高的 IOP 下，视网膜、ONH 和 ON 中受特定影响的时间和区域顺序机制提供了深入了解。
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