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MARCKS protein mediates hydrogen peroxide regulation of endothelial permeability

Benjamin Y Jin1, Alison J Lin, David E Golan

  • 1Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.

Proceedings of the National Academy of Sciences of the United States of America
|August 29, 2012
PubMed

Insights

Hydrogen peroxide increases endothelial permeability by affecting the actin cytoskeleton. Myristoylated alanine-rich C-kinase substrate (MARCKS) is identified as a key mediator in this oxidative stress-induced process.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Physiology

Background:

  • Endothelial barrier dysfunction is central to vascular and inflammatory diseases.
  • Oxidative stress, particularly from hydrogen peroxide (H(2)O(2)), is a known contributor to endothelial dysfunction.
  • The precise mechanisms by which H(2)O(2) increases endothelial permeability remain largely unknown.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying H(2)O(2)-induced endothelial permeability.
  • To identify key proteins involved in the H(2)O(2) signaling pathway that affects endothelial barrier function.

Main Methods:

  • Utilized bovine aortic endothelial cells for experiments.
  • Employed knockdown strategies (siRNA) and pharmacological inhibitors.
  • Investigated changes in actin cytoskeleton, protein phosphorylation, and cellular localization.

Main Results:

  • Identified myristoylated alanine-rich C-kinase substrate (MARCKS) as a critical mediator of H(2)O(2)-induced permeability.
  • Observed alterations in actin cytoskeleton architecture upon H(2)O(2) treatment and MARCKS knockdown.
  • Uncovered a signaling cascade involving Rac1, Abl1, phospholipase Cγ1, and PKCδ leading to MARCKS phosphorylation.

Conclusions:

  • MARCKS plays a pivotal role in regulating endothelial permeability under oxidative stress induced by H(2)O(2).
  • The identified signaling pathway provides new insights into endothelial dysfunction.
  • These findings suggest MARCKS and its associated pathway as potential therapeutic targets for oxidative stress-related vascular disorders.

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