title: Involvement of Oct4 in the pathogenesis of thoracic aortic dissection via inducing the dedifferentiated phenotype of human aortic smooth muscle cells by directly upregulating KLF5.
abstract: To investigate the expression of Oct4 in human thoracic aortic dissection (TAD) and the regulation mechanisms of Oct4 on phenotype transition of human aortic smooth muscle cells (HASMCs).
  
  
  
  Aortic samples from TAD patients (n = 12) and organ donors (n = 6) were collected. qRT-PCR, western blot, and immunohistochemistry were performed to identify Oct4 expression in aortic media. Immunofluorescence was performed to analyze Oct4 expression in primary HASMCs. Oct4A and Oct4B isoforms were detected. Gain-of-function experiments were performed to determine the effects of Oct4 on HASMC phenotype transition. Chromatin immunoprecipitation, luciferase assay, and rescue experiments were performed to analyze mechanisms of Oct4 on HASMC phenotype transition.
  
  
  
  Oct4 expression levels, especially the Oct4A isoform, were significantly higher in TAD patients compared with normal controls. Notably, Oct4 presented a strong and strict nuclear localization in primary HASMCs of TAD patients but a mild and diffuse distribution in both cytoplasm and nucleus in the control group. Overexpression of Oct4 induced dedifferentiation of HASMCs characterized by decreased contractile proteins and elevated migration capability. Krüppel-like factor 5 (KLF5) was found to be a directly regulated target gene of Oct4 in HASMCs. Furthermore, downregulation of KLF5 significantly alleviated the effects of Oct4 on phenotype transition of HASMCs.
  
  
  
  Oct4 expression was significantly upregulated in aortic tissues and primary HASMCs of TAD patients. The increased Oct4 induced phenotype transition of HASMCs from the contractile type to the synthetic type by directly upregulating KLF5.
authors.affiliation: Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, Zhejiang, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, Zhejiang, China. Electronic address: tmengweismmu@163.com.
authors.forename: Meng-Wei
authors.initials: MW
authors.lastname: Tan
authors.affiliation: Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, Zhejiang, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Xue
authors.affiliation: Cardiovascular Therapeutic Centre, The 117 Hospital of the Chinese People's Liberation Army, Hangzhou, Zhejiang, China.
authors.forename: Xue-Yan
authors.initials: XY
authors.lastname: Ding
authors.affiliation: Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, Zhejiang, China.
authors.forename: Guo-Kun
authors.initials: GK
authors.lastname: Wang
authors.affiliation: Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, Zhejiang, China. Electronic address: xuzhiyunsmmu@163.com.
authors.forename: Zhi-Yun
authors.initials: ZY
authors.lastname: Xu
mesh_terms: D000784:Aortic Dissection / Q000378:metabolism*; D017545:Aortic Aneurysm, Thoracic / Q000378:metabolism*; D015153:Blotting, Western; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D017540:Tunica Media / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors; D050814:Octamer Transcription Factor-3
keywords: KLF5; Oct4; human aortic smooth muscle cells; phenotype transition; thoracic aortic dissection