Increased exposure to ambient particulate matter (PM) is associated with elevated morbidity and mortality in patients with cardiopulmonary diseases and cancer. We and others have shown that PM induces lung microvascular barrier dysfunction which potentially enhances the systemic toxicity of PM. However, the mechanisms by which PM disrupts vascular endothelial integrity remain incompletely explored. We hypothesize that PM induces endothelial cell (EC) cytoskeleton rearrangement via Rho GTPase-dependent pathways to facilitate vascular hyperpermeability. Fine PM induced time-dependent activation of cytoskeletal machinery with increases in myosin light chain (MLC) phosphorylation and EC barrier disruption measured by transendothelial electrical resistance (TER), events attenuated by the Rho-dependent kinase (ROCK) inhibitor Y-27632 or the reactive oxygen species (ROS) scavenger, N-acetylcysteine (NAC). Both Y-27632 and NAC prevented PM-induced stress fiber formation and phospho-MLC accumulation in human lung ECs. PM promotes rapid accumulation of Rho-GTP. This event is attenuated by NAC or knockdown of RhoA (siRNA). Consistent with ROCK activation, PM induced phosphorylation of myosin light chain phosphatase (MYPT) at Thr850, a post-translational modification known to inhibit phosphatase activity. Furthermore, PM activates the guanine nucleotide exchange factor (GEF) for Rho, p115, with p115 translocation to the cell periphery, in a ROS-dependent manner. Together these results demonstrate that fine PM induces EC cytoskeleton rearrangement via Rho-dependent pathways that are dependent upon the generation of oxidative stress. As the disruption of vascular integrity further contributes to cardiopulmonary physiologic derangements, these findings provide pharmacologic targets for prevention of PM-induced cardiopulmonary toxicity.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/626005 |
| Date | 23 June 2017 |
| Creators | Wang, Ting, Shimizu, Yuka, Wu, Xiaomin, Kelly, Gabriel T., Xu, Xiaoyan, Wang, Lichun, Qian, Zhongqing, Chen, Yin, Garcia, Joe G.N. |
| Contributors | Univ Arizona, Dept Pharmacol & Toxicol, Department of Medicine, University of Arizona, Tucson, AZ, USA, Department of Medicine, University of Arizona, Tucson, AZ, USA, Department of Medicine, University of Arizona, Tucson, AZ, USA, Department of Medicine, University of Arizona, Tucson, AZ, USA, Department of Medicine, University of Arizona, Tucson, AZ, USA, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA, Key Laboratory of Anhui Province for Infection and Immunology, Bengbu Medical College, Anhui, China, Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA, Department of Medicine, University of Arizona, Tucson, AZ, USA |
| Publisher | SAGE PUBLICATIONS INC |
| Source Sets | University of Arizona |
| Language | English |
| Detected Language | English |
| Type | Article |
| Rights | © The Author(s) 2017. Creative Commons Non Commercial CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License. |
| Relation | http://journals.sagepub.com/doi/10.1086/689906 |
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