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Fragmented oxidation products define barrier disruptive endothelial cell response to OxPAPC.
Transl Res. 2013 Jun; 161(6):495-504.TR

Abstract

Excessive concentrations of oxidized phospholipids (OxPL), the products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine (PAPC) oxidation have been detected in atherosclerosis, septic inflammation, and acute lung injury (ALI) and have been shown to induce vascular barrier dysfunction. In contrast, oxidized PAPC (OxPAPC) at low concentrations exhibit potent barrier protective effects. The nature of such biphasic effects remains unclear. We tested the hypothesis that barrier-disruptive effects of high OxPAPC doses on endothelial cell (EC) monolayer are defined by fragmented products of PAPC oxidation (lysophosphatidyl choline [lyso-PC], 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-phosphatidylcholine [POVPC], 1-palmitoyl-2-glutaroyl-sn-glycero-phosphatidylcholine [PGPC]), whereas barrier enhancing effects are mediated by full length oxidated PAPC products and may be reproduced by single compounds contained in the OxPAPC such as 1-palmitoyl-2-(5,6-epoxyisoprostane E2)-sn-glycero-3-phosphatidyl choline (PEIPC). All 3 fragmented OxPAPC products increased EC permeability in a dose-dependent manner, whereas PEIPC decreased it and reversed barrier disruptive effects of lyso-PC, POVPC, and PGPC monitored by measurements of transendothelial electrical resistance. Immunofluorescence staining and western blot analysis showed that PGPC mimicked the cytoskeletal remodeling and tyrosine phosphorylation of adherens junction (AJ) protein vascular endothelial (VE)-cadherin leading to EC barrier dysfunction induced by high OxPAPC concentrations. Barrier-disruptive effects of PGPC were abrogated by reactive oxygen species (ROS) inhibitor, N-acetyl cysteine, or Src kinase inhibitor, PP-2. The results of this study show that barrier disruptive effects of fragmented OxPAPC constituents (lyso-PC, POVPC, PGPC) are balanced by barrier enhancing effects of full length oxygenated products (PEIPC). These data strongly suggest that barrier disruptive effects of OxPAPC at higher concentrations are dictated by predominant effects of fragmented phospholipids such as PGPC, which promote ROS-dependent activation of Src kinase and VE-cadherin phosphorylation at Tyr(658) and Tyr(731) leading to disruption of endothelial cell AJs.

Authors+Show Affiliations

Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

23305708

Citation

Birukova, Anna A., et al. "Fragmented Oxidation Products Define Barrier Disruptive Endothelial Cell Response to OxPAPC." Translational Research : the Journal of Laboratory and Clinical Medicine, vol. 161, no. 6, 2013, pp. 495-504.
Birukova AA, Starosta V, Tian X, et al. Fragmented oxidation products define barrier disruptive endothelial cell response to OxPAPC. Transl Res. 2013;161(6):495-504.
Birukova, A. A., Starosta, V., Tian, X., Higginbotham, K., Koroniak, L., Berliner, J. A., & Birukov, K. G. (2013). Fragmented oxidation products define barrier disruptive endothelial cell response to OxPAPC. Translational Research : the Journal of Laboratory and Clinical Medicine, 161(6), 495-504. https://doi.org/10.1016/j.trsl.2012.12.008
Birukova AA, et al. Fragmented Oxidation Products Define Barrier Disruptive Endothelial Cell Response to OxPAPC. Transl Res. 2013;161(6):495-504. PubMed PMID: 23305708.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fragmented oxidation products define barrier disruptive endothelial cell response to OxPAPC. AU - Birukova,Anna A, AU - Starosta,Vitaliy, AU - Tian,Xinyong, AU - Higginbotham,Katherine, AU - Koroniak,Lukas, AU - Berliner,Judith A, AU - Birukov,Konstantin G, Y1 - 2013/01/08/ PY - 2012/09/06/received PY - 2012/12/02/revised PY - 2012/12/13/accepted PY - 2013/1/12/entrez PY - 2013/1/12/pubmed PY - 2013/7/17/medline SP - 495 EP - 504 JF - Translational research : the journal of laboratory and clinical medicine JO - Transl Res VL - 161 IS - 6 N2 - Excessive concentrations of oxidized phospholipids (OxPL), the products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine (PAPC) oxidation have been detected in atherosclerosis, septic inflammation, and acute lung injury (ALI) and have been shown to induce vascular barrier dysfunction. In contrast, oxidized PAPC (OxPAPC) at low concentrations exhibit potent barrier protective effects. The nature of such biphasic effects remains unclear. We tested the hypothesis that barrier-disruptive effects of high OxPAPC doses on endothelial cell (EC) monolayer are defined by fragmented products of PAPC oxidation (lysophosphatidyl choline [lyso-PC], 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-phosphatidylcholine [POVPC], 1-palmitoyl-2-glutaroyl-sn-glycero-phosphatidylcholine [PGPC]), whereas barrier enhancing effects are mediated by full length oxidated PAPC products and may be reproduced by single compounds contained in the OxPAPC such as 1-palmitoyl-2-(5,6-epoxyisoprostane E2)-sn-glycero-3-phosphatidyl choline (PEIPC). All 3 fragmented OxPAPC products increased EC permeability in a dose-dependent manner, whereas PEIPC decreased it and reversed barrier disruptive effects of lyso-PC, POVPC, and PGPC monitored by measurements of transendothelial electrical resistance. Immunofluorescence staining and western blot analysis showed that PGPC mimicked the cytoskeletal remodeling and tyrosine phosphorylation of adherens junction (AJ) protein vascular endothelial (VE)-cadherin leading to EC barrier dysfunction induced by high OxPAPC concentrations. Barrier-disruptive effects of PGPC were abrogated by reactive oxygen species (ROS) inhibitor, N-acetyl cysteine, or Src kinase inhibitor, PP-2. The results of this study show that barrier disruptive effects of fragmented OxPAPC constituents (lyso-PC, POVPC, PGPC) are balanced by barrier enhancing effects of full length oxygenated products (PEIPC). These data strongly suggest that barrier disruptive effects of OxPAPC at higher concentrations are dictated by predominant effects of fragmented phospholipids such as PGPC, which promote ROS-dependent activation of Src kinase and VE-cadherin phosphorylation at Tyr(658) and Tyr(731) leading to disruption of endothelial cell AJs. SN - 1878-1810 UR - https://www.unboundmedicine.com/medline/citation/23305708/Fragmented_oxidation_products_define_barrier_disruptive_endothelial_cell_response_to_OxPAPC_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1931-5244(12)00422-7 DB - PRIME DP - Unbound Medicine ER -