The significance of protein S-palmitoylation in angiogenesis has been largely overlooked, leaving various aspects unexplored. Recent identification of Gpx1 as a palmitoylated protein has generated interest in exploring its potential involvement in novel pathological mechanisms related to angiogenesis. In this study, we demonstrate that Gpx1 undergoes palmitoylation at cysteine-76 and -113, with PPT1 playing a crucial role in modulating the depalmitoylation of Gpx1. Furthermore, we find that PPT1-regulated depalmitoylation negatively impacts Gpx1 protein stability. Interestingly, inhibiting Gpx1 palmitoylation, either through expression of a non-palmitoylated Gpx1 mutant or by expressing PPT1, significantly enhances neovascular angiogenesis. Conversely, in PPT1-deficient mice, angiogenesis is notably attenuated compared to wild-type mice in an Oxygen-Induced Retinopathy (OIR) model, which mimics pathological angiogenesis. Physiologically, under hypoxic conditions, Gpx1 palmitoylation levels are drastically reduced, suggesting that increasing Gpx1 palmitoylation may have beneficial effects. Indeed, enhancing Gpx1 palmitoylation by inhibiting PPT1 with DC661 effectively suppresses retinal angiogenesis in the OIR disease model. Overall, our findings highlight the pivotal role of protein palmitoylation in angiogenesis and propose a novel mechanism whereby the PPT1-Gpx1 axis modulates angiogenesis, thereby providing a potential therapeutic strategy for targeting PPT1 to combat angiogenesis.

中文翻译：

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通过靶向 PPT1 增强 Gpx1 棕榈酰化以抑制血管生成


蛋白质 S-棕榈酰化在血管生成中的重要性在很大程度上被忽视了，留下了未探索的各个方面。最近将 Gpx1 鉴定为棕榈酰化蛋白，这引起了人们对探索其可能参与与血管生成相关的新病理机制的兴趣。在这项研究中，我们证明 Gpx1 在半年半胱氨酸-76 和 -113 位点发生棕榈酰化，其中 PPT1 在调节 Gpx1 的去棕榈酰化中起关键作用。此外，我们发现 PPT1 调节的去棕榈酰化对 Gpx1 蛋白稳定性产生负面影响。有趣的是，通过表达非棕榈酰化 Gpx1 突变体或表达 PPT1 抑制 Gpx1 棕榈酰化，显着增强新生血管生成。相反，在模拟病理性血管生成的氧诱导视网膜病变 （OIR） 模型中，与 PPT1 缺陷小鼠相比，血管生成明显减弱。从生理学上讲，在缺氧条件下，Gpx1 棕榈酰化水平急剧降低，表明增加 Gpx1 棕榈酰化可能产生有益效果。事实上，通过用 DC661 抑制 PPT1 来增强 Gpx1 棕榈酰化可有效抑制 OIR 疾病模型中的视网膜血管生成。总体而言，我们的研究结果强调了蛋白质棕榈酰化在血管生成中的关键作用，并提出了一种新机制，即 PPT1-Gpx1 轴调节血管生成，从而为靶向 PPT1 对抗血管生成提供了潜在的治疗策略。