Enhancer of zeste homolog 2 facilitates phenotypic transition of vascular smooth muscle cells leading to aortic aneurysm/dissection

Xue,Shishan; Leng,Shuai; Zhang,Fengquan; Dang,Zhiqiao; Su,Guohai; Yu,Wenqian

doi:10.3892/etm.2024.12433

Enhancer of zeste homolog 2 facilitates phenotypic transition of vascular smooth muscle cells leading to aortic aneurysm/dissection

Authors:
- Shishan Xue
- Shuai Leng
- Fengquan Zhang
- Zhiqiao Dang
- Guohai Su
- Wenqian Yu
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Affiliations: Department of Cardiac Surgery, Research Center of Translational Medicine, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250013, P.R. China
Published online on: February 19, 2024 https://doi.org/10.3892/etm.2024.12433
Article Number: 145
Copyright: © Xue et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Thoracic aortic aneurysms (TAAs) are a major cause of death owing to weaker blood vessel walls and higher rupture rates in affected individuals. Vascular smooth muscle cells (VSMCs) are the predominant cell type within the aortic wall and their dysregulation may contribute to TAA progression. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, is involved in several pathological processes; however, the biological functions and mechanisms underlying VSMC phenotype transition and vascular intimal hyperplasia remain unclear. The present study aimed to determine the involvement of EZH2 in mediating VSMC function in the development of TAAs. The expression of EZH2 was revealed to be elevated in patients with thoracic aortic dissection and TAA mouse model through western blotting and reverse transcription‑quantitative PCR experiments. Subsequently, a mouse model was established using β‑aminopropionitrile. In vitro, EdU labeling, Transwell assay, wound healing assay and hematoxylin‑eosin staining revealed that knocking down the Ezh2 gene could reduce the proliferation, invasion, migration, and calcification of mouse primary aortic smooth muscle cells. Flow cytometry analysis found that EZH2 deficiency increased cell apoptosis. Depletion of Ezh2 in mouse primary aortic VSMCs promoted the transformation of VSMCs from a synthetic to a contractile phenotype. Using RNA‑sequencing analysis, it was demonstrated that Ezh2 regulated a group of genes, including integrin β3 (Itgb3), which are critically involved in the extracellular matrix signaling pathway. qChIP found Ezh2 occupies the Itgb3 promoter, thereby suppressing the expression of Itgb3. Ezh2 promotes the invasion and calcification of VSMCs, and this promoting effect is partially reversed by co‑knocking down Itgb3. In conclusion, the present study identified a previously unrecognized EZH2‑ITGB3 regulatory axis and thus provides novel mechanistic insights into the pathophysiological function of EZH2. EZH2 may thus serve as a potential target for the management of TAAs.

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