Article Text

PDF
45 REGULATION OF 4-HYDROXY-2-NONENAL-MEDIATED ENDOTHELIAL BARRIER FUNCTION BY FOCAL ADHESION AND ADHERENS JUNCTION PROTEINS.
  1. P. V. Usatyuk,
  2. V. Natarajan
  1. School of Medicine, The University of Chicago, Chicago, IL

Abstract

4-Hydroxy-2-nonenal (4-HNE), a highly reactive aldehyde generated by peroxidation of membrane lipids, altered endothelial cell (EC) barrier function, resulting in vascular leakiness. Here we report that 4-HNE mediates EC barrier dysfunction by modulating focal adhesion and adherens junction proteins that affect cell-cell and cell-matrix interactions via integrins. Treatment of bovine lung microvascular endothelial cells (BLMVECs) with 4-HNE, in a dose-dependent manner, modulated cell-cell adhesion contacts, enhanced intracellular ROS formation, and increased permeability. Interestingly, 4-HNE did not alter cell-matrix interactions as determined by transendothelial electrical resistance measurement. Therefore, we hypothesized that 4-HNE-induced permeability changes involved modulation of focal adhesion and adherens junction proteins. Treatment of BLMVECs with 4-HNE resulted in the redistribution of FAK, b-catenin, paxillin, VE-cadherin, and ZO-1 and caused intercellular gap formation. Western blot analyses confirmed that 4-HNE formed Michael adducts with the focal adhesion and adherens junction proteins. Furthermore, 4-HNE decreased tyrosine phosphorylation of FAK without affecting total cellular FAK contents. Flow cytometry and fluorescent microscopy analyses revealed a time-dependent reduction in the surface integrins after 4-HNE treatment.

Conclusion These results indicate that 4-HNE affects EC permeability by modulating cell-cell adhesion involving focal adhesion, adherens and tight junction proteins, as well as integrins signal transduction.

Supported by NIH RO1 HL 69909 and P01 HL 58064 to V.N.

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.