{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Sun J"],"funding":["Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada","Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (Conseil de Recherches en Sciences Naturelles et en Génie du Canada)","Gouvernement du Canada | Canadian Institutes of Health Research","Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)"],"pagination":["49"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9905587"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["9(1)"],"pubmed_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<sup>-/-</sup>) 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<sup>-/-</sup> mice, likely through mitotic arrest and subsequent induction of polyploidization and apoptosis."],"journal":["Cell death discovery"],"pubmed_title":["Polo-like kinase 4 inhibitor CFI-400945 inhibits carotid arterial neointima formation but increases atherosclerosis."],"pmcid":["PMC9905587"],"funding_grant_id":["PJT-178010","RGPIN-2020-04592","PJT-165941"],"pubmed_authors":["Zhou S","Chen YX","Gui Y","Zheng XL","Sun J","Belke D"],"additional_accession":[]},"is_claimable":false,"name":"Polo-like kinase 4 inhibitor CFI-400945 inhibits carotid arterial neointima formation but increases atherosclerosis.","description":"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<sup>-/-</sup>) 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<sup>-/-</sup> mice, likely through mitotic arrest and subsequent induction of polyploidization and apoptosis.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Feb","modification":"2026-06-24T03:12:40.746Z","creation":"2025-04-04T11:50:25.073Z"},"accession":"S-EPMC9905587","cross_references":{"pubmed":["36750553"],"doi":["10.1038/s41420-023-01305-4"]}}