TTK Inhibition Alleviates Postinjury Neointimal Formation and Atherosclerosis

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Vascular Biology

Background:

• Atherosclerosis and related complications are leading global causes of death.
• Current therapies inadequately reduce cardiovascular risk and fail to prevent restenosis or thrombosis post-intervention.
• Novel therapeutic targets are crucial for managing atherosclerosis and preventing vascular complications.

Purpose of the Study:

• To identify novel therapeutic targets for atherosclerosis and post-vascular injury restenosis and thrombosis.
• To investigate the role of TTK protein kinase (TTK) in vascular smooth muscle cell (VSMC) function and disease.

Main Methods:

• Investigated TTK's role in VSMC phenotypic switching and neointimal formation.
• Utilized VSMC-specific TTK deletion models in vascular injury and atherosclerosis studies (ApoE-/- mice).
• Assessed the efficacy of the TTK inhibitor CFI-402257 in preclinical models.

Main Results:

• TTK upregulation in VSMCs promotes neointimal formation and atherosclerosis by phosphorylating p120-catenin, causing β-catenin nuclear accumulation and MYOCD/SRF complex dissociation.
• VSMC-specific TTK deletion significantly reduced neointimal formation and atherosclerotic lesions.
• Oral administration of TTK inhibitor CFI-402257 reduced neointimal formation and atherosclerotic lesions without affecting reendothelialization or lipid levels.

Conclusions:

• TTK is a key regulator of VSMC phenotypic switching, contributing to atherosclerosis and post-injury restenosis.
• Targeting TTK, via inhibitors like CFI-402257, offers a promising strategy for simultaneously preventing restenosis and treating atherosclerosis.
• TTK inhibition presents a potential therapeutic avenue for cardiovascular disease management.