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

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posted on 09.01.2014 by Ting Wang, Lichun Wang, Liliana Moreno-Vinasco, Biji Mathew, Viswanathan Natarajan, Gabriel D. Lang, Jessica H. Siegler, Peter V. Usatyuk, Jonathan M. Samet, Alison S. Geyh, Patrick N. Breysse, Joe G. N. Garcia
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.

Funding

Environmental Protection Agency/Johns Hopkins Particulate Matter Center Grant # RD83241701 (JGNG and JMS), NIH HL058064 (JGNG), and Parker B. Francis Foundation (TW).

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Publisher Statement

© 2012 Wang et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This is a copy of an article published in the Particle and Fibre Toxicology © 2012 BioMed Central

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BioMed Central

Language

en_US

issn

1743-8977

Issue date

01/08/2012

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