Particulate matter air pollution disrupts endothelial cell barrier via calpain-mediated tight junction protein degradation

Ting Wang, Lichun Wang, Liliana Moreno-Vinasco, Gabriel D. Lang, Jessica H. Siegler, Biji Mathew, Peter V. Usatyuk, Jonathan M. Samet, Alison S. Geyh, Patrick N. Breysse, Viswanathan Natarajan, Joe G.N. Garcia

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

Background: Exposure to particulate matter (PM) is a significant risk factor for increased cardiopulmonary morbidity and mortality. The mechanism of PM-mediated pathophysiology remains unknown. However, PM is proinflammatory to the endothelium and increases vascular permeability in vitro and in vivo via ROS generation.Objectives: We explored the role of tight junction proteins as targets for PM-induced loss of lung endothelial cell (EC) barrier integrity and enhanced cardiopulmonary dysfunction.Methods: Changes in human lung EC monolayer permeability were assessed by Transendothelial Electrical Resistance (TER) in response to PM challenge (collected from Ft. McHenry Tunnel, Baltimore, MD, particle size >0.1 μm). Biochemical assessment of ROS generation and Ca2+ mobilization were also measured.Results: PM exposure induced tight junction protein Zona occludens-1 (ZO-1) relocation from the cell periphery, which was accompanied by significant reductions in ZO-1 protein levels but not in adherens junction proteins (VE-cadherin and β-catenin). N-acetyl-cysteine (NAC, 5 mM) reduced PM-induced ROS generation in ECs, which further prevented TER decreases and atteneuated ZO-1 degradation. PM also mediated intracellular calcium mobilization via the transient receptor potential cation channel M2 (TRPM2), in a ROS-dependent manner with subsequent activation of the Ca2+-dependent protease calpain. PM-activated calpain is responsible for ZO-1 degradation and EC barrier disruption. Overexpression of ZO-1 attenuated PM-induced endothelial barrier disruption and vascular hyperpermeability in vivo and in vitro.Conclusions: These results demonstrate that PM induces marked increases in vascular permeability via ROS-mediated calcium leakage via activated TRPM2, and via ZO-1 degradation by activated calpain. These findings support a novel mechanism for PM-induced lung damage and adverse cardiovascular outcomes.

Original languageEnglish
Article number35
JournalParticle and Fibre Toxicology
Volume9
DOIs
StatePublished - Aug 29 2012
Externally publishedYes

Keywords

  • Calpain
  • Endothelial permeability
  • Particulate matter
  • ROS
  • TRPM2

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    Wang, T., Wang, L., Moreno-Vinasco, L., Lang, G. D., Siegler, J. H., Mathew, B., Usatyuk, P. V., Samet, J. M., Geyh, A. S., Breysse, P. N., Natarajan, V., & Garcia, J. G. N. (2012). Particulate matter air pollution disrupts endothelial cell barrier via calpain-mediated tight junction protein degradation. Particle and Fibre Toxicology, 9, [35]. https://doi.org/10.1186/1743-8977-9-35