Polo-like kinase 4 inhibitor CFI-400945 inhibits carotid arterial neointima formation but increases atherosclerosis

Abstract

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.

Pharmacological inhibition of MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) induces ferroptosis in vascular smooth muscle cells

“…We were interested in examining the impact of MI-2 on proliferative diseases in vivo. To do this, we generated neointimal lesions by completely ligating the carotid arteries of C57BL/6J mice, as we have previously described [33,38] (Fig. 7A).…”

“…Partial carotid ligation and atherosclerosis model in ApoE −/− mice fed a high-fat diet Four-month-old ApoE −/− male mice were randomly allocated to vehicle control (DMSO), MI-2, or MI-2 plus Fer-1 treatment groups (the investigator was not blinded to the group assignments). A partial carotid ligation was performed as previously described [38,59]. The anesthesia protocols utilized were identical to those outlined for complete ligation.…”