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Published on: July 9, 2020
TTK Inhibition Alleviates Postinjury Neointimal Formation and Atherosclerosis
Jie-Hong Wu1, Yu-Xiao Liu1, Jia-Bin Zong1
1Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Insights
This study reveals TTK protein kinase (TTK) as a critical factor in vascular smooth muscle cell changes, offering a new target for treating atherosclerosis and preventing restenosis after vascular injury.
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.
Abstract:
Atherosclerosis and its associated cardio-cerebrovascular complications remain the leading causes of mortality worldwide. Current lipid-lowering therapies reduce only approximately one-third of the cardiovascular risk. Furthermore, vascular restenosis and thrombotic events following surgical interventions for severe vascular stenosis significantly contribute to treatment failure. This highlights the urgent need for novel therapeutic targets to manage atherosclerosis and prevent restenosis and thrombosis after vascular injury. This study identifies TTK protein kinase (TTK) as a key regulator of vascular smooth muscle cell (VSMC) phenotypic switching in the context of postinjury neointimal formation and atherosclerosis. Mechanistically, TTK upregulation in VSMCs phosphorylates p120-catenin, leading to β-catenin nuclear accumulation and dissociation of the myocardin (MYOCD)/serum response factor (SRF) complex. Deletion of TTK specifically in VSMCs reduces postinjury neointimal formation in vascular injury models and attenuates atherosclerotic lesions in ApoE-/- mice. Notably, oral administration of the TTK inhibitor CFI-402257 mitigated neointimal formation without impairing reendothelialization and reduced atherosclerotic lesions in ApoE-/- mice without altering lipid levels. These findings suggest that targeting TTK, through inhibitors or alternative strategies, represents a promising approach to simultaneously prevent postinjury restenosis and treat atherosclerosis.
