Neointima lesion and
atherosclerosis are proliferative
vascular diseases associated with deregulated proliferation of vascular smooth muscle cells (SMCs).
CFI-400945 is a novel, highly effective anticancer
drug that inhibits polo-like
kinase 4 (PLK4) and targets mitosis. In this study, we aim to investigate how
CFI-400945 affects the development of proliferative
vascular diseases. In C57BL/6 mice,
neointima formation was generated by complete carotid
ligation. In
apolipoprotein E knockout (
ApoE-/-) mice fed a high-fat diet,
atherosclerosis was induced by partial carotid
ligation.
CFI-400945 was directly applied to carotid arteries via a perivascular collar. Our results showed that
CFI-400945 drastically inhibited
neointima formation but significantly accelerated
atherosclerosis. In vitro studies showed that
CFI-400945 treatment induced SMC polyploidization and arrested cells in the G2/M phase.
CFI-400945 treatment upregulated p53 and p27 expression but decreased p21 and
cyclin B1 expression.
CFI-400945 also induced SMC apoptosis, which was inhibited by
hydroxyurea,
a DNA synthesis inhibitor that inhibits polyploidization. Furthermore,
CFI-400945 caused supernumerary centrosomes, leading to mitotic failure, resulting in polyploidization. In conclusion,
CFI-400945 prevents carotid arterial
neointima formation in C57BL/6 mice but accelerates
atherosclerosis in
ApoE-/- mice, likely through mitotic arrest and subsequent induction of polyploidization and apoptosis.