MARCKS protein mediates hydrogen peroxide regulation of endothelial permeability

作者：Jin Benjamin Y; Lin Alison J^*; Golan David E; Michel Thomas

来源：Proceedings of the National Academy of Sciences, 2012, 109(37): 14864-14869.

DOI：10.1073/pnas.1204974109

Impairment of endothelial barrier function is implicated in many vascular and inflammatory disorders. One prevalent mechanism of endothelial dysfunction is an increase in reactive oxygen species under oxidative stress. Previous reports have demonstrated that hydrogen peroxide (H2O2), a highly stable reactive oxygen species that modulates physiological signaling pathways, also enhances endothelial permeability, but the mechanism of this effect is unknown. Here, we identify the actin-binding protein myristoylated alanine-rich C-kinase substrate (MARCKS) as a key mediator of the H2O2-induced permeability change in bovine aortic endothelial cells. MARCKS knockdown and H2O2 treatment alter the architecture of the actin cytoskeleton in endothelial cells, and H2O2 induces the phosphorylation and translocation of MARCKS from the cell membrane to the cytosol. Using pharmacological inhibitors and small interference RNA constructs directed against specific proteins, we uncover a signaling cascade from Rac1 to Abl1, phospholipase C gamma 1, and PKC delta that is triggered by H2O2 and leads to MARCKS phosphorylation. Our findings establish a distinct role for MARCKS in the regulation of H2O2-induced permeability change in endothelial cells, and suggest potential new therapeutic targets for the treatment of disorders involving oxidative stress and altered endothelial permeability.

• 出版日期2012-9-11