Promotional Effects of HIF1α and KDM3A Interaction on Vascular Smooth Muscle Cells in Thoracic Aortic Dissection

Abstract

Aim: The current study was performed to define the role of KDM3A in thoracic aortic dissection (TAD). Methods: The binding of HIF1α and KDM3A in HES1 was detected by ChIP and dual-luciferase reporter gene assay. Loss and gain-of function assays of HIF1α, KDM3A and HES1 were further performed in Ang-II-induced mouse aortic smooth muscle cell line (MOVAS) cells. Lastly, in vivo TAD models were established. Results: HIF1α was highly expressed in TAD. KDM3A promoted the transcription activation of HES1. HIF1α 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 HIF1α in vivo and in vitro. Conclusion: The findings indicated that interaction between HIF1α 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 HIF1α increased the formation and movement of Ang-II-induced mouse aortic smooth muscle cell line cells, whereas HIF1α silencing caused the opposite results. The KDM3A gene supported the transcriptional activation of HES1 by interacting with HIF1α. HIF1α increased TAD formation in vivo and the silencing of the HES1 transcription factor reversed the effects of HIF1α 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.

Keywords::

• demethylation
• HES1
• HIF1α
• KDM3A
• migration
• proliferation
• thoracic aortic dissection
• vascular smooth muscle cells

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2021-0147

Author Contributions

ZY Liang and Q Liang contributed to the conception and design of the study; W Zhang contributed to the acquisition of data; L Zheng contributed to the analysis and interpretation of data; ZY Liang and XJ Shen contributed to drafting the article; Q Liang and YJ Zhang contributed to revising the article critically for important intellectual content. All authors approved the final version to be submitted.

Financial&competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The present study was approved by the ethics committee of The First Affiliated Hospital of Xi’an Jiaotong University and conformed to principles originating in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Data sharing statement

The data that supports the findings of this study are available in the manuscript and supplementary materials.