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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 ?m). 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 ?-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

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

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

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