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.

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.

MeSH terms

  • Aged
  • Animals
  • Apoptosis* / physiology
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Endocytosis* / physiology
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / pathology
  • Plaque, Atherosclerotic* / metabolism
  • Plaque, Atherosclerotic* / pathology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1* / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1* / metabolism
  • Receptor, Platelet-Derived Growth Factor beta* / metabolism
  • rab5 GTP-Binding Proteins* / genetics
  • rab5 GTP-Binding Proteins* / metabolism

Substances

  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • rab5 GTP-Binding Proteins
  • Receptor, Platelet-Derived Growth Factor beta
  • PTPN1 protein, human
  • Ptpn1 protein, mouse
  • RAB5C protein, human