Dataset Information

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

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.

SUBMITTER: Wang T

PROVIDER: S-EPMC3489700 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Wang Ting T Wang Lichun L Moreno-Vinasco Liliana L Lang Gabriel D GD Siegler Jessica H JH Mathew Biji B Usatyuk Peter V PV Samet Jonathan M JM Geyh Alison S AS Breysse Patrick N PN Natarajan Viswanathan V Garcia Joe G N JG

Particle and fibre toxicology 20120829

<h4>Background</h4>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.<h4>Objectives</h4>We explored the role of tight junction proteins as targets for PM-induced loss of lung endothelial cell (EC) barrier integrity and enhanced cardiopulmonar ...[more]

PMID: 22931549

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Dataset Information

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

Background

Objectives

Methods

Results

Conclusions

Publications

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

Similar Datasets

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