TTK Inhibition Alleviates Postinjury Neointimal Formation and Atherosclerosis

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