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血栓反应蛋白 1 在 Rho 相关蛋白激酶抑制剂抑制时介导自噬。

Thrombospondin 1 Mediates Autophagy Upon Inhibition of the Rho-Associated Protein Kinase Inhibitor.

机构信息

School of Optometry, The Hong Kong Polytechnic University, Hong Kong, China.

Centre for Eye and Vision Research (CEVR), 17W Hong Kong Science Park, Hong Kong, China.

出版信息

Cells. 2024 Nov 18;13(22):1907. doi: 10.3390/cells13221907.

DOI:10.3390/cells13221907
PMID:39594655
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11593289/
Abstract

Age-related macular degeneration (AMD) is a degenerative eye disease leading to central vision loss and is characterized by dysregulated autophagy of the retinal pigment epithelium (RPE) layer. Recent studies have suggested that rho-associated protein kinase (ROCK) inhibitors may enhance autophagy in neurodegenerative diseases and promote the survival of RPE cells. This study investigated the effect of ROCK inhibitors on autophagy gene expression and autophagic vacuole formation in a human RPE (ARPE-19) cell line. The highly selective and potent ROCK inhibitor Y-39983 enhanced the expression of autophagy genes in ARPE-19 cells and increased autophagic vacuole formation. A proteomic analysis using mass spectrometry was performed to further characterize the effects of ROCK inhibition at the protein level. Y-39983 downregulated thrombospondin-1 (THBS1), and suppression of THBS1 in ARPE-19 cells resulted in an increase in autophagic vacuole formation. Our data showed that ROCK inhibitor-induced autophagy was mediated by THBS1 downregulation. We identified ROCK and THBS1 as potential novel therapeutic targets in AMD.

摘要

年龄相关性黄斑变性（AMD）是一种退行性眼病，导致中心视力丧失，其特征是视网膜色素上皮（RPE）层的自噬失调。最近的研究表明，rho 相关蛋白激酶（ROCK）抑制剂可能增强神经退行性疾病中的自噬，并促进 RPE 细胞的存活。本研究探讨了 ROCK 抑制剂对人 RPE（ARPE-19）细胞系中自噬基因表达和自噬小体形成的影响。高选择性和高效的 ROCK 抑制剂 Y-39983 增强了 ARPE-19 细胞中自噬基因的表达，并增加了自噬小体的形成。通过质谱的蛋白质组学分析进一步表征了 ROCK 抑制在蛋白质水平上的作用。Y-39983 下调了血小板反应蛋白-1（THBS1），并且在 ARPE-19 细胞中抑制 THBS1 导致自噬小体形成增加。我们的数据表明，ROCK 抑制剂诱导的自噬是通过 THBS1 的下调介导的。我们确定 ROCK 和 THBS1 是 AMD 的潜在新的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f34d/11593289/f468a900d4a9/cells-13-01907-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f34d/11593289/31172a6f867e/cells-13-01907-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f34d/11593289/c097ee432f67/cells-13-01907-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f34d/11593289/d8d8a8e16a85/cells-13-01907-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f34d/11593289/2e2fa9fb74d3/cells-13-01907-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f34d/11593289/5f3464cfb24d/cells-13-01907-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f34d/11593289/f468a900d4a9/cells-13-01907-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f34d/11593289/31172a6f867e/cells-13-01907-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f34d/11593289/1338a2e6e562/cells-13-01907-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f34d/11593289/c097ee432f67/cells-13-01907-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f34d/11593289/d8d8a8e16a85/cells-13-01907-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f34d/11593289/2e2fa9fb74d3/cells-13-01907-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f34d/11593289/5f3464cfb24d/cells-13-01907-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f34d/11593289/f468a900d4a9/cells-13-01907-g007.jpg

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