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Signaling pathways involved in OxPAPC-induced pulmonary endothelial barrier protection.
Microvasc Res. 2007 May; 73(3):173-81.MR

Abstract

Increased tissue or serum levels of oxidized phospholipids have been detected in a variety of chronic and acute pathological conditions such as hyperlipidemia, atherosclerosis, heart attack, cell apoptosis, acute inflammation and injury. We have recently described signaling cascades activated by oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC)in the human pulmonary artery endothelial cells (EC) and reported potent barrier-protective effects of OxPAPC, which were mediated by small GTPases Rac and Cdc42. In this study we have further characterized signal transduction pathways involved in the OxPAPC-mediated endothelial barrier protection. Inhibitors of small GTPases, protein kinase A (PKA), protein kinase C (PKC), Src family kinases and general inhibitors of tyrosine kinases attenuated OxPAPC-induced barrier-protective response and EC cytoskeletal remodeling. In contrast, small GTPase Rho, Rho kinase, Erk-1,2 MAP kinase and p38 MAP kinase and PI3-kinase were not involved in the barrier-protective effects of OxPAPC. Inhibitors of PKA, PKC, tyrosine kinases and small GTPase inhibitor toxin B suppressed OxPAPC-induced Rac activation and decreased phosphorylation of focal adhesion kinase (FAK) and paxillin. Barrier-protective effects of OxPAPC were not reproduced by platelet activating factor (PAF), which at high concentrations induced barrier dysfunction, but were partially attenuated by PAF receptor antagonist A85783. These results demonstrate for the first time upstream signaling cascades involved in the OxPAPC-induced Rac activation, cytoskeletal remodeling and barrier regulation and suggest PAF receptor-independent mechanisms of OxPAPC-mediated endothelial barrier protection.

Authors+Show Affiliations

Section of Pulmonary and Critical Medicine, Department of Medicine, Division of Biomedical Sciences, University of Chicago, 929 East 57th Street, CIS Bldg., W410, Chicago, IL 60637, USA.No 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

17292425

Citation

Birukova, Anna A., et al. "Signaling Pathways Involved in OxPAPC-induced Pulmonary Endothelial Barrier Protection." Microvascular Research, vol. 73, no. 3, 2007, pp. 173-81.
Birukova AA, Chatchavalvanich S, Oskolkova O, et al. Signaling pathways involved in OxPAPC-induced pulmonary endothelial barrier protection. Microvasc Res. 2007;73(3):173-81.
Birukova, A. A., Chatchavalvanich, S., Oskolkova, O., Bochkov, V. N., & Birukov, K. G. (2007). Signaling pathways involved in OxPAPC-induced pulmonary endothelial barrier protection. Microvascular Research, 73(3), 173-81.
Birukova AA, et al. Signaling Pathways Involved in OxPAPC-induced Pulmonary Endothelial Barrier Protection. Microvasc Res. 2007;73(3):173-81. PubMed PMID: 17292425.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Signaling pathways involved in OxPAPC-induced pulmonary endothelial barrier protection. AU - Birukova,Anna A, AU - Chatchavalvanich,Santipongse, AU - Oskolkova,Olga, AU - Bochkov,Valery N, AU - Birukov,Konstantin G, Y1 - 2007/01/03/ PY - 2006/11/27/received PY - 2006/12/20/accepted PY - 2007/2/13/pubmed PY - 2007/6/28/medline PY - 2007/2/13/entrez SP - 173 EP - 81 JF - Microvascular research JO - Microvasc Res VL - 73 IS - 3 N2 - Increased tissue or serum levels of oxidized phospholipids have been detected in a variety of chronic and acute pathological conditions such as hyperlipidemia, atherosclerosis, heart attack, cell apoptosis, acute inflammation and injury. We have recently described signaling cascades activated by oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC)in the human pulmonary artery endothelial cells (EC) and reported potent barrier-protective effects of OxPAPC, which were mediated by small GTPases Rac and Cdc42. In this study we have further characterized signal transduction pathways involved in the OxPAPC-mediated endothelial barrier protection. Inhibitors of small GTPases, protein kinase A (PKA), protein kinase C (PKC), Src family kinases and general inhibitors of tyrosine kinases attenuated OxPAPC-induced barrier-protective response and EC cytoskeletal remodeling. In contrast, small GTPase Rho, Rho kinase, Erk-1,2 MAP kinase and p38 MAP kinase and PI3-kinase were not involved in the barrier-protective effects of OxPAPC. Inhibitors of PKA, PKC, tyrosine kinases and small GTPase inhibitor toxin B suppressed OxPAPC-induced Rac activation and decreased phosphorylation of focal adhesion kinase (FAK) and paxillin. Barrier-protective effects of OxPAPC were not reproduced by platelet activating factor (PAF), which at high concentrations induced barrier dysfunction, but were partially attenuated by PAF receptor antagonist A85783. These results demonstrate for the first time upstream signaling cascades involved in the OxPAPC-induced Rac activation, cytoskeletal remodeling and barrier regulation and suggest PAF receptor-independent mechanisms of OxPAPC-mediated endothelial barrier protection. SN - 0026-2862 UR - https://www.unboundmedicine.com/medline/citation/17292425/Signaling_pathways_involved_in_OxPAPC_induced_pulmonary_endothelial_barrier_protection_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0026-2862(06)00149-X DB - PRIME DP - Unbound Medicine ER -