Promotional effects of HIF1 and KDM3A interaction on vascular smooth muscle cells in thoracic aortic dissection
EPIGENOMICS(2022)
Abstract
Aim: The current study was performed to define the role of KDM3A in thoracic aortic dissection (TAD). Methods: The binding of HIF1 alpha and KDM3A in HES1 was detected by ChIP and dual-luciferase reporter gene assay. Loss and gain-of function assays of HIF1 alpha, KDM3A and HES1 were further performed in Ang-IIinduced mouse aortic smooth muscle cell line (MOVAS) cells. Lastly, in vivo TAD models were established. Results: HIF1 alpha was highly expressed in TAD. KDM3A promoted the transcription activation of HES1. HIF1 alpha enhanced the proliferation and migration of Ang-II-induced MOVAS cells, in addition to increasing thoracic aorta dilation to induce TAD formation in vivo. Silencing of HES1 reversed the effects of HIF1 alpha in vivo and in vitro. Conclusion: The findings indicated that interaction between HIF1 alpha and KDM3A enhances the proliferation and migration of MOVAS cells to induce TAD. Plain language summary: The current study aimed to clarify the role of the KDM3A gene, which is involved in thoracic aortic dissection (TAD; a sudden tear in the inner layer of the aortic wall) as well as its underlying mechanism. The findings revealed that overexpression of HIF1 alpha increased the formation and movement of Ang-II-induced mouse aortic smooth muscle cell line cells, whereas HIF1 alpha silencing caused the opposite results. The KDM3A gene supported the transcriptional activation of HES1 by interacting with HIF1 alpha. HIF1 alpha increased TAD formation in vivo and the silencing of the HES1 transcription factor reversed the effects of HIF1 alpha in vivo and in vitro. These discoveries deepen our understanding of the causes of TAD and highlight novel therapeutic targets for the development of effective targeted therapy against TAD.
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Key words
demethylation,HES1,HIF1 alpha,KDM3A,migration,proliferation,thoracic aortic dissection,vascular smooth muscle cells
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