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Prostaglandin E receptor-4 receptor mediates endothelial barrier-enhancing and anti-inflammatory effects of oxidized phospholipids.
FASEB J. 2017 09; 31(9):4187-4202.FJ

Abstract

Unlike other agonists that cause transient endothelial cell (EC) response, the products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC) oxidation that contain cyclopenthenone groups, which recapitulate prostaglandin-like structure, cause sustained enhancement of the pulmonary EC barrier. The mechanisms that drive the sustained effects by oxidized PAPC (OxPAPC) remain unexplored. On the basis of the structural similarity of isoprostanoid moieties that are present in full-length oxygenated PAPC species, we used an inhibitory approach to perform the screening of prostanoid receptors as potential candidates that mediate OxPAPC effects. Results show that only prostaglandin E receptor-4 (EP4) was involved and mediated the sustained phase of the barrier-enhancing effects of OxPAPC that are associated with the activation of Rac GTPase and its cytoskeletal targets. EC incubation with OxPAPC also induced EP4 mRNA expression in pulmonary ECs and lung tissue. EP4 knockdown using gene-specific small interfering RNA did not affect the rapid phase of OxPAPC-induced EC barrier enhancement or the protective effects against thrombin-induced EC permeability, but abolished the advanced barrier enhancement phase and suppressed the protective effects of OxPAPC against more sustained EC barrier dysfunction and cell inflammatory response caused by TNF-α. Endothelial-specific knockout of the EP4 receptor in mice attenuated the protective effect of intravenous OxPAPC administration in the model of acute lung injury caused by intratracheal injection of LPS. Taken together, these results demonstrate a novel role for prostaglandin receptor EP4 in the mediation of barrier-enhancing and anti-inflammatory effects caused by oxidized phospholipids.-Oskolkova, O., Gawlak, G., Tian, Y., Ke, Y., Sarich, N., Son, S., Andreasson, K., Bochkov, V. N., Birukova, A. A., Birukov, K. G. Prostaglandin E receptor-4 receptor mediates endothelial barrier-enhancing and anti-inflammatory effects of oxidized phospholipids.

Authors+Show Affiliations

Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA.Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA.Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA.Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA.Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA.Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA.Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.Department of Pharmaceutical Chemistry, University of Graz, Graz, Austria.Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA.Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA; kbirukov@anes.umm.edu.

Pub Type(s)

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

Language

eng

PubMed ID

28572443

Citation

Oskolkova, Olga, et al. "Prostaglandin E Receptor-4 Receptor Mediates Endothelial Barrier-enhancing and Anti-inflammatory Effects of Oxidized Phospholipids." FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, vol. 31, no. 9, 2017, pp. 4187-4202.
Oskolkova O, Gawlak G, Tian Y, et al. Prostaglandin E receptor-4 receptor mediates endothelial barrier-enhancing and anti-inflammatory effects of oxidized phospholipids. FASEB J. 2017;31(9):4187-4202.
Oskolkova, O., Gawlak, G., Tian, Y., Ke, Y., Sarich, N., Son, S., Andreasson, K., Bochkov, V. N., Birukova, A. A., & Birukov, K. G. (2017). Prostaglandin E receptor-4 receptor mediates endothelial barrier-enhancing and anti-inflammatory effects of oxidized phospholipids. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 31(9), 4187-4202. https://doi.org/10.1096/fj.201601232RR
Oskolkova O, et al. Prostaglandin E Receptor-4 Receptor Mediates Endothelial Barrier-enhancing and Anti-inflammatory Effects of Oxidized Phospholipids. FASEB J. 2017;31(9):4187-4202. PubMed PMID: 28572443.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Prostaglandin E receptor-4 receptor mediates endothelial barrier-enhancing and anti-inflammatory effects of oxidized phospholipids. AU - Oskolkova,Olga, AU - Gawlak,Grzegorz, AU - Tian,Yufeng, AU - Ke,Yunbo, AU - Sarich,Nicolene, AU - Son,Sophia, AU - Andreasson,Katrin, AU - Bochkov,Valery N, AU - Birukova,Anna A, AU - Birukov,Konstantin G, Y1 - 2017/06/01/ PY - 2016/11/10/received PY - 2017/05/08/accepted PY - 2017/6/3/pubmed PY - 2017/10/14/medline PY - 2017/6/3/entrez KW - acute lung injury KW - cytoskeleton KW - vascular permeability SP - 4187 EP - 4202 JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JO - FASEB J VL - 31 IS - 9 N2 - Unlike other agonists that cause transient endothelial cell (EC) response, the products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC) oxidation that contain cyclopenthenone groups, which recapitulate prostaglandin-like structure, cause sustained enhancement of the pulmonary EC barrier. The mechanisms that drive the sustained effects by oxidized PAPC (OxPAPC) remain unexplored. On the basis of the structural similarity of isoprostanoid moieties that are present in full-length oxygenated PAPC species, we used an inhibitory approach to perform the screening of prostanoid receptors as potential candidates that mediate OxPAPC effects. Results show that only prostaglandin E receptor-4 (EP4) was involved and mediated the sustained phase of the barrier-enhancing effects of OxPAPC that are associated with the activation of Rac GTPase and its cytoskeletal targets. EC incubation with OxPAPC also induced EP4 mRNA expression in pulmonary ECs and lung tissue. EP4 knockdown using gene-specific small interfering RNA did not affect the rapid phase of OxPAPC-induced EC barrier enhancement or the protective effects against thrombin-induced EC permeability, but abolished the advanced barrier enhancement phase and suppressed the protective effects of OxPAPC against more sustained EC barrier dysfunction and cell inflammatory response caused by TNF-α. Endothelial-specific knockout of the EP4 receptor in mice attenuated the protective effect of intravenous OxPAPC administration in the model of acute lung injury caused by intratracheal injection of LPS. Taken together, these results demonstrate a novel role for prostaglandin receptor EP4 in the mediation of barrier-enhancing and anti-inflammatory effects caused by oxidized phospholipids.-Oskolkova, O., Gawlak, G., Tian, Y., Ke, Y., Sarich, N., Son, S., Andreasson, K., Bochkov, V. N., Birukova, A. A., Birukov, K. G. Prostaglandin E receptor-4 receptor mediates endothelial barrier-enhancing and anti-inflammatory effects of oxidized phospholipids. SN - 1530-6860 UR - https://www.unboundmedicine.com/medline/citation/28572443/Prostaglandin_E_receptor_4_receptor_mediates_endothelial_barrier_enhancing_and_anti_inflammatory_effects_of_oxidized_phospholipids_ L2 - https://doi.org/10.1096/fj.201601232RR DB - PRIME DP - Unbound Medicine ER -