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PMID: 21997484 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

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 ·2012-03-00 ·Pages 331-41

Starosta V, Wu T, Zimman A, Pham D, Tian X, Oskolkova O, Bochkov V, Berliner JA, Birukova AA, Birukov KG

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.

MeSH Terms
Adherens Junctions/drug effects,metabolism Antigens, CD/metabolism Cadherins/metabolism Capillary Permeability/drug effects Catenins/metabolism Cells, Cultured Dose-Response Relationship, Drug Electric Impedance Endothelial Cells/drug effects,metabolism Humans Phosphatidylcholines/pharmacology Phosphorylation Reactive Oxygen Species/metabolism Time Factors Tyrosine beta Catenin/metabolism src-Family Kinases/metabolism
Chemicals
Antigens, CD CTNNB1 protein, human Cadherins Catenins Phosphatidylcholines Reactive Oxygen Species beta Catenin cadherin 5 delta catenin oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine Tyrosine src-Family Kinases
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Starosta Vitaliy
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.
Wu Tinghuai
Zimman Alejandro
Pham Donald
Tian Xinyong
Oskolkova Olga
Bochkov Valery
Berliner Judith A
Birukova Anna A
Birukov Konstantin G
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Article Info
Journal
American journal of respiratory cell and molecular biology
Abbr.
Am J Respir Cell Mol Biol
ISSN
1535-4989
DOI
10.1165/rcmb.2011-0153OC
Published
2012-03-00
Epub
2011-00-13
Pages
331-41
Language
English
Region
United States
NLM ID
8917225
PMCID
PMC3326435
Subset
IM
Grants
NHLBI NIH HHS · P01 HL58064 · United States
NHLBI NIH HHS · R01 HL089257 · United States
NHLBI NIH HHS · HL87823 · United States
NHLBI NIH HHS · P01 HL058064 · United States
NHLBI NIH HHS · HL89257 · United States
NHLBI NIH HHS · R01 HL107920 · United States
NHLBI NIH HHS · R01 HL076259 · United States
NHLBI NIH HHS · HL76259 · United States
NHLBI NIH HHS · R56 HL107920 · United States
NHLBI NIH HHS · R01 HL087823 · United States
NHLBI NIH HHS · HL107920 · United States
NHLBI NIH HHS · P01 HL030568 · United States
External Links
PubMed source DOI: 10.1165/rcmb.2011-0153OC PMC Full Text View journal details
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