PTP1B Modulates Carotid Plaque Vulnerability in Atherosclerosis Through Rab5-PDGFRβ-Mediated Endocytosis Disruption and Apoptosis

IF 4.8 1区医学 Q1 NEUROSCIENCES CNS Neuroscience & Therapeutics Pub Date : 2024-11-08 DOI:10.1111/cns.70071

Xiao Zhang, Ran Xu, Tao Wang, Jiayao Li, Yixin Sun, Shengyan Cui, Zixuan Xing, Xintao Lyu, Ge Yang, Liqun Jiao, Wenjing Li

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Abstract

Background

Protein tyrosine phosphatase 1B (PTP1B) is a protein tyrosine phosphatase and modulates platelet-derived growth factor (PDGF)/platelet-derived growth factor receptor (PDGFR) signaling in vascular smooth muscle cells (VSMCs) via endocytosis. However, the related molecular pathways that participated in the interaction of endo-lysosome and the trafficking of PDGFR are largely unknown. This study aims to determine the subcellular regulating mechanism of PTP1B to the endo-lysosome degradation of PDGFR in atherosclerotic carotid plaques, thereby offering a potential therapeutic target for the stabilization of carotid plaques.

Methods

The immunohistochemical staining technique was employed to assess the expression levels of both PDGFR-β and Caspase 3 in stable and vulnerable carotid plaques. Tunnel staining was utilized to quantify the apoptosis of carotid plaques. Live-cell imaging was employed to observe endocytic motility, while cell apoptosis was evaluated through Propidium Iodide staining. In an in vivo experiment, ApoE^−/− mice were administered a PTP1B inhibitor to investigate the impact of PTP1B on atherosclerosis.

Results

The heightened expression of PDGFR-β correlates with apoptosis in patients with vulnerable carotid plaques. At the subcellular level of VSMCs, PDGFR-β plays a pivotal role in sustaining a balanced endocytosis system motility, regulated by the expression of Rab5, a key regulator of endocytic motility. And PTP1B modulates PDGFR-β signaling via Rab5-mediated endocytosis. Additionally, disrupted endocytic motility influences the interplay between endosomes and lysosomes, which is crucial for controlling PDGFR-β trafficking. Elevated PTP1B expression induces cellular apoptosis and impedes migration and proliferation of carotid VSMCs. Ultimately, mice with PTP1B deficiency exhibit a reduction in atherosclerosis.

Conclusion

Our results illustrate that PTP1B induces disruption in endocytosis and apoptosis of VSMCs through the Rab5-PDGFRβ pathway, suggesting a potential association with the heightened vulnerability of carotid plaques.

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PTP1B通过Rab5-PDGFRβ介导的内吞破坏和细胞凋亡调节动脉粥样硬化中颈动脉斑块的易损性

背景：蛋白酪氨酸磷酸酶1B（PTP1B）是一种蛋白酪氨酸磷酸酶，通过内吞作用调节血管平滑肌细胞（VSMC）中血小板衍生生长因子（PDGF）/血小板衍生生长因子受体（PDGFR）的信号转导。然而，参与内含溶酶体相互作用和 PDGFR 转运的相关分子通路目前尚不清楚。本研究旨在确定PTP1B对动脉粥样硬化性颈动脉斑块中PDGFR内溶酶体降解的亚细胞调控机制，从而为稳定颈动脉斑块提供潜在的治疗靶点：方法：采用免疫组化染色技术评估稳定和易损颈动脉斑块中 PDGFR-β 和 Caspase 3 的表达水平。隧道染色用于量化颈动脉斑块的细胞凋亡。活细胞成像用于观察内细胞运动，而细胞凋亡则通过碘化丙啶染色进行评估。在体内实验中，给载脂蛋白E-/-小鼠注射了PTP1B抑制剂，以研究PTP1B对动脉粥样硬化的影响：结果：PDGFR-β的高表达与易损颈动脉斑块患者的细胞凋亡有关。在 VSMCs 的亚细胞水平，PDGFR-β 在维持平衡的内吞系统运动中起着关键作用，它受内吞运动的关键调控因子 Rab5 的表达调控。PTP1B 通过 Rab5 介导的内吞作用调节 PDGFR-β 信号。此外，内吞运动紊乱会影响内体和溶酶体之间的相互作用，而这对控制 PDGFR-β 的贩运至关重要。PTP1B 表达升高会诱导细胞凋亡，并阻碍颈动脉 VSMC 的迁移和增殖。最终，缺乏 PTP1B 的小鼠动脉粥样硬化症状减轻：我们的研究结果表明，PTP1B 可通过 Rab5-PDGFRβ 通路诱导 VSMC 的内吞和凋亡，这可能与颈动脉斑块的脆弱性增加有关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.