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Differential regulation of endothelial cell permeability by high and low doses of oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine.
Am J Respir Cell Mol Biol. 2012 Mar; 46(3):331-41.AJ

Abstract

The generation of phospholipid oxidation products in atherosclerosis, sepsis, and lung pathologies affects endothelial barrier function, which exerts significant consequences on disease outcomes in general. Our group previously showed that oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine (OxPAPC) at low concentrations increases endothelial cell (EC) barrier function, but decreases it at higher concentrations. In this study, we determined the mechanisms responsible for the pulmonary endothelial cell barrier dysfunction induced by high OxPAPC concentrations. OxPAPC at a range of 5-20 μg/ml enhanced EC barriers, as indicated by increased transendothelial electrical resistance. In contrast, higher OxPAPC concentrations (50-100 μg/ml) rapidly increased EC permeability, which was accompanied by increased total cell protein tyrosine (Tyr) phosphorylation, phosphorylation at Tyr-418, the activation of Src kinase, and the phosphorylation of adherens junction (AJ) protein vascular endothelial cadherin (VE-cadherin) at Tyr-731 and Tyr-658, which was not observed in ECs stimulated with low OxPAPC doses. The early tyrosine phosphorylation of VE-cadherin was linked to the dissociation of VE-cadherin-p120-catenin/β-catenin complexes and VE-cadherin internalization, whereas low OxPAPC doses promoted the formation of VE-cadherin-p120-catenin/β-catenin complexes. High but not low doses of OxPAPC increased the production of reactive oxygen species (ROS) and protein oxidation. The inhibition of Src by PP2 and ROS production by N-acetyl cysteine inhibited the disassembly of VE-cadherin-p120-catenin complexes, and attenuated high OxPAPC-induced EC barrier disruption. These results show the differential effects of OxPAPC doses on VE-cadherin-p120-catenin complex assembly and EC barrier function. These data suggest that the rapid tyrosine phosphorylation of VE-cadherin and other potential targets mediated by Src and ROS-dependent mechanisms plays a key role in the dissociation of AJ complexes and EC barrier dysfunction induced by high OxPAPC doses.

Authors+Show Affiliations

Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, 5841 S. Maryland Ave., Office N611, Chicago, IL 60637, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo 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

21997484

Citation

Starosta, Vitaliy, et al. "Differential Regulation of Endothelial Cell Permeability By High and Low Doses of Oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine." American Journal of Respiratory Cell and Molecular Biology, vol. 46, no. 3, 2012, pp. 331-41.
Starosta V, Wu T, Zimman A, et al. Differential regulation of endothelial cell permeability by high and low doses of oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine. Am J Respir Cell Mol Biol. 2012;46(3):331-41.
Starosta, V., Wu, T., Zimman, A., Pham, D., Tian, X., Oskolkova, O., Bochkov, V., Berliner, J. A., Birukova, A. A., & Birukov, K. G. (2012). Differential regulation of endothelial cell permeability by high and low doses of oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine. American Journal of Respiratory Cell and Molecular Biology, 46(3), 331-41. https://doi.org/10.1165/rcmb.2011-0153OC
Starosta V, et al. Differential Regulation of Endothelial Cell Permeability By High and Low Doses of Oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine. Am J Respir Cell Mol Biol. 2012;46(3):331-41. PubMed PMID: 21997484.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential regulation of endothelial cell permeability by high and low doses of oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine. AU - Starosta,Vitaliy, AU - Wu,Tinghuai, AU - Zimman,Alejandro, AU - Pham,Donald, AU - Tian,Xinyong, AU - Oskolkova,Olga, AU - Bochkov,Valery, AU - Berliner,Judith A, AU - Birukova,Anna A, AU - Birukov,Konstantin G, Y1 - 2011/10/13/ PY - 2011/10/15/entrez PY - 2011/10/15/pubmed PY - 2012/4/24/medline SP - 331 EP - 41 JF - American journal of respiratory cell and molecular biology JO - Am J Respir Cell Mol Biol VL - 46 IS - 3 N2 - The generation of phospholipid oxidation products in atherosclerosis, sepsis, and lung pathologies affects endothelial barrier function, which exerts significant consequences on disease outcomes in general. Our group previously showed that oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine (OxPAPC) at low concentrations increases endothelial cell (EC) barrier function, but decreases it at higher concentrations. In this study, we determined the mechanisms responsible for the pulmonary endothelial cell barrier dysfunction induced by high OxPAPC concentrations. OxPAPC at a range of 5-20 μg/ml enhanced EC barriers, as indicated by increased transendothelial electrical resistance. In contrast, higher OxPAPC concentrations (50-100 μg/ml) rapidly increased EC permeability, which was accompanied by increased total cell protein tyrosine (Tyr) phosphorylation, phosphorylation at Tyr-418, the activation of Src kinase, and the phosphorylation of adherens junction (AJ) protein vascular endothelial cadherin (VE-cadherin) at Tyr-731 and Tyr-658, which was not observed in ECs stimulated with low OxPAPC doses. The early tyrosine phosphorylation of VE-cadherin was linked to the dissociation of VE-cadherin-p120-catenin/β-catenin complexes and VE-cadherin internalization, whereas low OxPAPC doses promoted the formation of VE-cadherin-p120-catenin/β-catenin complexes. High but not low doses of OxPAPC increased the production of reactive oxygen species (ROS) and protein oxidation. The inhibition of Src by PP2 and ROS production by N-acetyl cysteine inhibited the disassembly of VE-cadherin-p120-catenin complexes, and attenuated high OxPAPC-induced EC barrier disruption. These results show the differential effects of OxPAPC doses on VE-cadherin-p120-catenin complex assembly and EC barrier function. These data suggest that the rapid tyrosine phosphorylation of VE-cadherin and other potential targets mediated by Src and ROS-dependent mechanisms plays a key role in the dissociation of AJ complexes and EC barrier dysfunction induced by high OxPAPC doses. SN - 1535-4989 UR - https://www.unboundmedicine.com/medline/citation/21997484/Differential_regulation_of_endothelial_cell_permeability_by_high_and_low_doses_of_oxidized_1_palmitoyl_2_arachidonyl_sn_glycero_3_phosphocholine_ L2 - https://www.atsjournals.org/doi/10.1165/rcmb.2011-0153OC?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -