2. Academic Validation
  3. PTP1B Modulates Carotid Plaque Vulnerability in Atherosclerosis Through Rab5-PDGFRβ-Mediated Endocytosis Disruption and Apoptosis

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

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.

Figures
Products