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

Jiaxing Sun; Darrell Belke; Yu Gui; Yong-Xiang Chen; Shenghua Zhou; Xi-Long Zheng

doi:10.1038/s41420-023-01305-4

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

Cell Death Discov. 2023 Feb 7;9(1):49. doi: 10.1038/s41420-023-01305-4.

Authors

Jiaxing Sun^{1

2}, Darrell Belke³, Yu Gui¹, Yong-Xiang Chen³, Shenghua Zhou⁴, Xi-Long Zheng⁵

Affiliations

¹ Departments of Biochemistry and Molecular Biology and Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
² Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, China.
³ Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
⁴ Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, China. zhoushenghua@csu.edu.cn.
⁵ Departments of Biochemistry and Molecular Biology and Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. xlzheng@ucalgary.ca.

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.

Abstract

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