title: Nrf3-Pla2g7 interaction plays an essential role in smooth muscle differentiation from stem cells.
abstract: OBJECTIVE
  Phospholipase A2, group 7 (Pla2g7) is an important mediator in cardiovascular development and diseases because of its divergent physiological and pathological functions in inflammation and oxidative stress. However, little is known about the functional role of Pla2g7 in smooth muscle cell (SMC) differentiation from stem cells.
  
  
  RESULTS
  In the present study, embryonic stem cells were cultivated on collagen IV-coated plates to allow SMC differentiation. Pla2g7 gene expression and activity were upregulated significantly following 4 to 14 days of cell differentiation and colocalized with SMC differentiation markers in the differentiated SMCs. Knockdown of Pla2g7 resulted in downregulation of smooth muscle-specific markers in vitro and impairment of SMC differentiation in vivo, whereas enforced expression of Pla2g7 enhanced SMC differentiation and increased reactive oxygen species generation. Importantly, enforced expression of Pla2g7 significantly increased the binding of serum response factor to SMC differentiation gene promoters, resulting in SMC differentiation, which was abolished by free radical scavenger and flavoprotein inhibitor of NADPH oxidase but not hydrogen peroxide inhibitor. Moreover, we demonstrated that nuclear factor erythroid 2-related factor 3 (Nrf3) regulates Pla2g7 gene expression through direct binding to the promoter regions of Pla2g7 gene.
  
  
  CONCLUSIONS
  Our findings demonstrated that Pla2g7 plays a crucial physiological role in SMC differentiation from stem cells, and the fine interactions between Nrf3 and Pla2g7 are essential for SMC differentiation.
authors.affiliation: Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom. q.xiao@qmul.ac.uk
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Xiao
authors.forename: Anna E
authors.initials: AE
authors.lastname: Pepe
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Zhenling
authors.initials: Z
authors.lastname: Luo
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Lingfang
authors.initials: L
authors.lastname: Zeng
authors.forename: Zhongyi
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Hu
authors.forename: Shu
authors.initials: S
authors.lastname: Ye
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Xu
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018919:Neovascularization, Physiologic; D054467:Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D027602:Serum Response Element; D026362:Serum Response Factor / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D015854:Up-Regulation
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D015415:Biomarkers; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; C485120:Nrf3 protein, mouse; D026362:Serum Response Factor; D013481:Superoxides; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D054467:Phospholipases A2; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C571209:Pla2g7 protein, mouse