EZH2 Promotes Phenotype Transition Of Vascular Smooth Muscle Cells Leading To Aortic Aneurysm/Dissection

Background:Thoracic aortic aneurysm(TAA)is the principal cause of mortality and morbidity worldwide,which is more dangerous due to their fragile vessel wall and the high-risk to rupture,has a high mortality rate.Vascular smooth muscle cells(VSMCs)are the primary participants in TAA.The present study analyzed the role of enhancer of zeste homolog 2(EZH2)in vascular remodeling of TAA by investigating the behavior of VASMs.The expression levels of EZH2 in VSMCs in TAA were detected.The role of EZH2 in VSMCs proliferation and migration was investigated following EZH2 knockdown.To investigate the impact of EZH2 knockdown on VSMCs,RNA sequencing was employed to perform functional enrichment analysis on the whole-genome expression profiles.The results were confirmed using quantitative PCR(qPCR).EZH2 expression levels were found to be elevated in both TAD patients and TAA mice models.The analysis of differentially expressed genes after EZH2 knockdown revealed a compelling association between EZH2 and specific cellular functions,such as cell adhension molecules and or ECM-receptor interaction in VSMCs.The qPCR analysis confirmed the mRNA expression levels of Itgb3.It was observed that the migration of VSMCs in TAA was affected by EZH2,indicating that EZH2 could be a promising therapeutic target for TAA treatment.Objective:The purpose of this study is to explore the effects and mechanisms of EZH2 on VSMCs phenotype switching in TAA and to provide a new perspective for the TAA.Methods:(1)Collect the arterial tissue samples of clinical patients with TAD,and explore the correlation between EZH2 and TAD diseases.(2)Establish mouse TAA model,and explore the correlation between EZH2 and TAA diseases in mice.(3)Primary mouse smooth muscle cells were isolated,and the expression of EZH2 gene was knocked out in vitro,so as to explore the effect of EZH2 on proliferation,apoptosis and phenotypic transformation of smooth muscle cells.(4)Through Gene Ontology(GO),Kyoto Encyclopedia of Genes and Genomes(KEGG)and Gene Set Enrichment Analysis(GSEA),the target genes directly regulated by EZH2 were screened out.(5)Carry out rescue experiments on the selected target genes to explore the role of EZH2-Itgb3-axis in the occurrence and development of TAA.data sets.Results:(1)EZH2 expression is increased in human TAD.(2)EZH2 expression is increased in mouse TAA.(3)Knockdown of EZH2 influences VSMC phenotypic switching.(4)Genome-wide identifification of EZH2 transcription target.(5)EZH2 regulates Itgb3 and participates in VSMCs invasion.Conclusion:Elucidating the underlying molecular mechanisms of related epigenetic modifications has provided new insights into the understanding of TAA pathogenesis,creating new strategies for TAA prevention and treatment.In summary,this study revealed that EZH2 recruits the Itgb3 in VSMCs,which provides new insights into how the EZH2 selects its interacting ECM-molecules in VSMCs.Our results show that the EZH2-ECM-receptor-Itgb3 axis is involved in VSMCs proliferation and phenotype switching.Our data provide a molecular basis for understanding the pathophysiological function of EZH2 and support the view that the EZH2-ECMreceptor-Itgb3 axis can serve as a potential therapeutic target in TAA.