Polychlorinated biphenyl quinone induces endothelial barrier dysregulation by setting the cross talk between VE-cadherin, focal adhesion, and MAPK signaling.

Abstract

Environmental hazardous material polychlorinated biphenyl (PCB) exposure is associated with vascular endothelial dysfunction, which may increase the risk of cardiovascular diseases and cancer metastasis. Our previous studies illustrated the cytotoxic, antiproliferative, and genotoxic effects of a synthetic, quinone-type, highly reactive metabolite of PCB, 2,3,5-trichloro-6-phenyl-[1,4]benzoquinone (PCB29-pQ). Here, we used it as the model compound to investigate its effects on vascular endothelial integrity and permeability. We demonstrated that noncytotoxic doses of PCB29-pQ induced vascular endothelial (VE)-cadherin junction disassembly by increasing the phosphorylation of VE-cadherin at Y658. We also found that focal adhesion assembly was required for PCB29-pQ-induced junction breakdown. Focal adhesion site-associated actin stress fibers may serve as holding points for cytoskeletal tension to regulate the cellular contractility. PCB29-pQ exposure promoted the association of actin stress fibers with paxillin-containing focal adhesion sites and enlarged the size/number of focal adhesions. In addition, PCB29-pQ treatment induced phosphorylation of paxillin at Y118. By using pharmacological inhibition, we further demonstrated that p38 activation was necessary for paxillin phosphorylation, whereas extracellular signal-regulated kinases-1/2 activation regulated VE-cadherin phosphorylation. In conclusion, these results indicated that PCB29-pQ stimulates endothelial hyperpermeability by mediating VE-cadherin disassembly, junction breakdown, and focal adhesion formation. Intervention strategies targeting focal adhesion and MAPK signaling could be used as therapeutic approaches for preventing adverse cardiovascular health effects induced by environmental toxicants such as PCBs.

• Authors: Pu Zhang, Shan Feng, Huiyuan Bai, Panying Zeng, Feng Chen, Chengxiang Wu, Yi Peng, Qin Zhang, Qiuyao Zhang, Qichao Ye, Qiang Xue, Xiaoyu Xu, Erqun Song, Yang Song
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 308 Issue 10 Pg. H1205-14 (May 15 2015) ISSN: 1522-1539 [Electronic] United States
• PMID: 25770237 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 the American Physiological Society.

Chemical References

• 2,3,5-trichloro-6-phenyl-(1,4)benzoquinone
• Antigens, CD
• Benzoquinones
• Cadherins
• Paxillin
• cadherin 5
• Polychlorinated Biphenyls

Topics

• Antigens, CD (genetics, metabolism)
• Benzoquinones (pharmacology)
• Cadherins (genetics, metabolism)
• Capillary Permeability
• Focal Adhesions (drug effects, metabolism)
• Human Umbilical Vein Endothelial Cells (drug effects, metabolism)
• Humans
• MAP Kinase Signaling System
• Paxillin (metabolism)
• Polychlorinated Biphenyls (pharmacology)