Sp1-mediated nonmuscle myosin light chain kinase expression and enhanced activity in vascular endothelial growth factor–induced vascular permeability

Yuka Shimizua, Sara M. Campa, Xiaoguang Sun, Tong Zhou, Ting Wang, Joe GN Garcia

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Despite the important role played by the nonmuscle isoform of myosin light chain kinase (nmMLCK) in vascular barrier regulation and the implication of both nmMLCK and vascular endothelial growth factor (VEGF) in the pathogenesis of acute respiratory distress syndrome (ARDS), the role played by nmMLCK in VEGF-induced vascular permeability is poorly understood. In this study, the role played by nmMLCK in VEGF-induced vascular hyperpermeability was investigated. Human lung endothelial cell barrier integrity in response to VEGF is examined in both the absence and the presence of nmMLCK small interfering RNAs. Levels of nmMLCK messenger RNA (mRNA), protein, and promoter activity expression were monitored after VEGF stimulation in lung endothelial cells. nmMYLK promoter activity was assessed using nmMYLK promoter luciferase reporter constructs with a series of nested deletions. nmMYLK transcriptional regulation was further characterized by examination of a key transcriptional factor. nmMLCK plays an important role in VEGFinduced permeability. We found that activation of the VEGF signaling pathway in lung endothelial cells increases MYLK gene product at both mRNA and protein levels. Increased nmMLCK mRNA and protein expression is a result of increased nmMYLK promoter activity, regulated in part by binding of the Sp1 transcription factor on triggering by the VEGF signaling pathway. Taken together, these findings suggest that MYLK is an important ARDS candidate gene and a therapeutic target that is highly influenced by excessive VEGF concentrations in the inflamed lung.

Original languageEnglish (US)
Pages (from-to)707-715
Number of pages9
JournalPulmonary Circulation
Volume5
Issue number4
DOIs
StatePublished - Oct 23 2015

Keywords

  • ARDS
  • Endothelial
  • MYLK
  • Myosin light chain kinase (MLCK)
  • Permeability
  • Promoter
  • Sp1
  • Transcription factor
  • Vascular endothelial growth factor (VEGF)

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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