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

  • CNS Neurosci Ther. 2024 Nov;30(11):e70071. doi: 10.1111/cns.70071.
Xiao Zhang  1  2 ,  Ran Xu  1  2 ,  Tao Wang  1  2 ,  Jiayao Li  1  2 ,  Yixin Sun  3  4 ,  Shengyan Cui  1  2 ,  Zixuan Xing  5 ,  Xintao Lyu  6 ,  Ge Yang  7  8 ,  Liqun Jiao  1  2  9 ,  Wenjing Li  7  8
Affiliations
  • 1. Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China.
  • 2. China International Neuroscience Institute (China-INI), Beijing, China.
  • 3. First Hospital, Peking University, Beijing, China.
  • 4. Health Science Center, Peking University, Beijing, China.
  • 5. Health Science Center, Xi'an Jiaotong University, Shanxi, China.
  • 6. Capital Medical University, Beijing, China.
  • 7. Laboratory of Computational Biology and Machine Intelligence, National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China.
  • 8. School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing, China.
  • 9. Department of Interventional Neuroradiology, Xuanwu Hospital, Capital Medical University, Beijing, China.
PMID: 39517122 DOI: 10.1111/cns.70071
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.

Keywords
PTP1B; apoptosis; atherosclerosis; carotid plaque; endocytosis disruption.
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