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Inhibition of endothelial barrier dysfunction by P21-activated kinase-1

Yunbo Ke1, Hazel Lum, R John Solaro

  • 1Department of Physiology and Biophysics M/C 901 and Center for Cardiovascular Research, University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, IL 60612, USA. yke@uic.edu

Canadian Journal of Physiology and Pharmacology
|July 7, 2007
PubMed

Insights

P21-activated kinase-1 (Pak1) regulates endothelial barrier function by dephosphorylating myosin light chain. This action inhibits thrombin-induced barrier dysfunction, highlighting Pak1

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Endothelial barrier dysfunction is implicated in various vascular diseases.
  • P21-activated kinase-1 (Pak1) is a known regulator of cellular processes.
  • Myosin light chain phosphorylation plays a critical role in endothelial cell contraction and barrier integrity.

Purpose of the Study:

  • To investigate the role of Pak1 in regulating myosin light chain phosphorylation.
  • To determine Pak1's effect on thrombin-induced endothelial barrier dysfunction in human microvascular endothelial cells (HMEC).
  • To elucidate the mechanism by which Pak1 influences endothelial barrier function.

Main Methods:

  • Human microvascular endothelial cells (HMEC) were infected with recombinant adenoviruses expressing constitutively active Pak1, wild-type, or mutant myosin regulatory light chain (mMLC20).
  • Myosin light chain phosphorylation levels were assessed.
  • Endothelial barrier function was evaluated by measuring responses to thrombin stimulation.
  • Interactions between Pak1 and phosphatase 2A (PP2A) were examined.

Main Results:

  • Active Pak1 expression led to dephosphorylation of myosin light chain 20 (MLC20) in HMEC.
  • Active Pak1 significantly inhibited thrombin-induced endothelial barrier dysfunction.
  • Expression of an unphosphorylatable MLC20 mutant also inhibited thrombin-induced barrier dysfunction.
  • Constitutively active Pak1 associated with and induced post-translational modification of phosphatase 2A.

Conclusions:

  • Pak1 dephosphorylates MLC20 in endothelial cells, contributing to barrier protection.
  • Pak1 activation inhibits thrombin-induced endothelial barrier dysfunction.
  • Pak1 regulates endothelial barrier function through the activation of phosphatase 2A.

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