Repurpose of Ritlecitinib Reduces Neointima Formation and Enhances Endothelial Recovery Following Vascular Injury

Area of Science:

• Vascular Biology
• Pharmacology
• Immunology

Background:

• Neointimal hyperplasia, characterized by smooth muscle cell (SMC) proliferation and poor endothelial recovery, is a key factor in vascular injury response.
• Janus kinase 3 (JAK3) signaling is implicated in vascular remodeling.
• This study investigates the potential of selective JAK3 inhibition to mitigate neointimal hyperplasia and enhance reendothelialization.

Purpose of the Study:

• To evaluate the efficacy of Ritlecitinib, a selective JAK3 inhibitor, in preventing neointimal hyperplasia and promoting endothelial repair.
• To elucidate the molecular mechanisms underlying Ritlecitinib's effects on SMCs and endothelial cells.
• To explore genetic factors influencing patient response to JAK3 inhibition.

Main Methods:

• Utilized mouse carotid wire injury and human internal mammary artery (IMA) xenograft models to assess Ritlecitinib's effects.
• Investigated JAK3 signaling pathways, including JNK/c-Jun, thrombospondin-1 (TSP-1), and vascular endothelial growth factor A (VEGF-A), using molecular biology techniques (RNA-seq, CUT&RUN).
• Conducted rescue experiments and analyzed patient-derived IMA SMCs for drug response variability.

Main Results:

• Ritlecitinib treatment significantly reduced neointimal area and improved endothelial coverage in both animal models.
• JAK3 inhibition suppressed JNK/c-Jun signaling, modulated TSP-1 and VEGF-A expression, favoring endothelial regeneration.
• Genetic variations in JAK3 and VEGF-A correlated with differential responses to Ritlecitinib in patient-derived cells.

Conclusions:

• Selective JAK3 inhibition with Ritlecitinib offers a dual therapeutic approach by restraining SMC proliferation and promoting endothelial repair.
• Ritlecitinib demonstrates potential as a precision therapy for preventing restenosis.
• Genetic stratification may identify optimal responders for Ritlecitinib treatment.