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p190RhoGAP mediates protective effects of oxidized phospholipids in the models of ventilator-induced lung injury.
Exp Cell Res. 2011 Apr 01; 317(6):859-72.EC

Abstract

Products resulting from oxidation of cell membrane phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) exhibit potent protective effects against lung endothelial cell (EC) barrier dysfunction caused by pathologically relevant mechanical forces and inflammatory agents. These effects were linked to enhancement of peripheral cytoskeleton and cell adhesion interactions mediated by small GTPase Rac and inhibition of Rho-mediated barrier-disruptive signaling. However, the mechanism of OxPAPC-induced, Rac-dependent Rho downregulation critical for vascular barrier protection remains unclear. This study tested the hypothesis that Rho negative regulator p190RhoGAP is essential for OxPAPC-induced lung barrier protection against ventilator-induced lung injury (VILI), and investigated potential mechanism of p190RhoGAP targeting to adherens junctions (AJ) via p120-catenin. OxPAPC induced peripheral translocation of p190RhoGAP, which was abolished by knockdown of Rac-specific guanine nucleotide exchange factors Tiam1 and Vav2. OxPAPC also induced Rac-dependent tyrosine phosphorylation and association of p190RhoGAP with AJ protein p120-catenin. siRNA-induced knockdown of p190RhoGAP attenuated protective effects of OxPAPC against EC barrier compromise induced by thrombin and pathologically relevant cyclic stretch (18% CS). In vivo, p190RhoGAP knockdown significantly attenuated protective effects of OxPAPC against ventilator-induced lung vascular leak, as detected by increased cell count and protein content in the bronchoalveolar lavage fluid, and tissue neutrophil accumulation in the lung. These results demonstrate for the first time a key role of p190RhoGAP for the vascular endothelial barrier protection in VILI.

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
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21111731

Citation

Birukova, Anna A., et al. "P190RhoGAP Mediates Protective Effects of Oxidized Phospholipids in the Models of Ventilator-induced Lung Injury." Experimental Cell Research, vol. 317, no. 6, 2011, pp. 859-72.
Birukova AA, Zebda N, Cokic I, et al. P190RhoGAP mediates protective effects of oxidized phospholipids in the models of ventilator-induced lung injury. Exp Cell Res. 2011;317(6):859-72.
Birukova, A. A., Zebda, N., Cokic, I., Fu, P., Wu, T., Dubrovskyi, O., & Birukov, K. G. (2011). P190RhoGAP mediates protective effects of oxidized phospholipids in the models of ventilator-induced lung injury. Experimental Cell Research, 317(6), 859-72. https://doi.org/10.1016/j.yexcr.2010.11.011
Birukova AA, et al. P190RhoGAP Mediates Protective Effects of Oxidized Phospholipids in the Models of Ventilator-induced Lung Injury. Exp Cell Res. 2011 Apr 1;317(6):859-72. PubMed PMID: 21111731.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - p190RhoGAP mediates protective effects of oxidized phospholipids in the models of ventilator-induced lung injury. AU - Birukova,Anna A, AU - Zebda,Noureddine, AU - Cokic,Ivan, AU - Fu,Panfeng, AU - Wu,Tinghuai, AU - Dubrovskyi,Oleksii, AU - Birukov,Konstantin G, Y1 - 2010/11/25/ PY - 2010/07/30/received PY - 2010/11/01/revised PY - 2010/11/18/accepted PY - 2010/11/30/entrez PY - 2010/11/30/pubmed PY - 2011/5/26/medline SP - 859 EP - 72 JF - Experimental cell research JO - Exp Cell Res VL - 317 IS - 6 N2 - Products resulting from oxidation of cell membrane phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) exhibit potent protective effects against lung endothelial cell (EC) barrier dysfunction caused by pathologically relevant mechanical forces and inflammatory agents. These effects were linked to enhancement of peripheral cytoskeleton and cell adhesion interactions mediated by small GTPase Rac and inhibition of Rho-mediated barrier-disruptive signaling. However, the mechanism of OxPAPC-induced, Rac-dependent Rho downregulation critical for vascular barrier protection remains unclear. This study tested the hypothesis that Rho negative regulator p190RhoGAP is essential for OxPAPC-induced lung barrier protection against ventilator-induced lung injury (VILI), and investigated potential mechanism of p190RhoGAP targeting to adherens junctions (AJ) via p120-catenin. OxPAPC induced peripheral translocation of p190RhoGAP, which was abolished by knockdown of Rac-specific guanine nucleotide exchange factors Tiam1 and Vav2. OxPAPC also induced Rac-dependent tyrosine phosphorylation and association of p190RhoGAP with AJ protein p120-catenin. siRNA-induced knockdown of p190RhoGAP attenuated protective effects of OxPAPC against EC barrier compromise induced by thrombin and pathologically relevant cyclic stretch (18% CS). In vivo, p190RhoGAP knockdown significantly attenuated protective effects of OxPAPC against ventilator-induced lung vascular leak, as detected by increased cell count and protein content in the bronchoalveolar lavage fluid, and tissue neutrophil accumulation in the lung. These results demonstrate for the first time a key role of p190RhoGAP for the vascular endothelial barrier protection in VILI. SN - 1090-2422 UR - https://www.unboundmedicine.com/medline/citation/21111731/p190RhoGAP_mediates_protective_effects_of_oxidized_phospholipids_in_the_models_of_ventilator_induced_lung_injury_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4827(10)00540-9 DB - PRIME DP - Unbound Medicine ER -