title: Inhibition of AMP-activated protein kinase accentuates lipopolysaccharide-induced lung endothelial barrier dysfunction and lung injury in vivo.
abstract: The aim of this study was to determine the role of AMP-activated protein kinase (AMPK) in lipopolysaccharide (LPS)-induced lung endothelial barrier dysfunction and lung injury in vivo. Both cultured human pulmonary artery endothelial cells (HPAECs) and experimental animals [AMPK subunit α-deficient mice and wild-type (WT) control mice (C57BL/6J)] were used. In cultured HPAECs, LPS increased endothelial permeability in parallel with a decrease in AMPK activity. Consistent with this observation, AMPK activation with the potent AMPK activator 5-aminoimidazole-4-carboxamide-1-d-ribofuranoside (AICAR) attenuated LPS-induced endothelial hyperpermeability in vitro. Intratracheal administration of LPS (1 mg/kg) in WT mice reduced AMPK phosphorylation at Thr172 in lung tissue extracts, increased protein content and cell count in bronchial alveolar lavage fluid, and increased Evans Blue dye infiltration into the lung. These same attributes were similarly enhanced in AMPKα-knockout mice, compared with WT mice. Pretreatment with AICAR reduced these lung injury indicators in LPS-treated WT mice. AMPK activation with AICAR attenuated LPS-induced endothelial hyperpermeability by activating the Rac/Cdc42/PAK pathway, with concomitant inhibition of the Rho pathway, and decreased VE-cadherin phosphorylation at Tyr658. We conclude that AMPK activity supports normal endothelial barrier function and that LPS exposure inhibits AMPK, thereby contributing to endothelial barrier dysfunction and lung injury.
authors.affiliation: Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
authors.forename: Junjie
authors.initials: J
authors.lastname: Xing
authors.forename: Qilong
authors.initials: Q
authors.lastname: Wang
authors.forename: Kathleen
authors.initials: K
authors.lastname: Coughlan
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Cate
authors.initials: C
authors.lastname: Moriasi
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zou
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001808:Blood Vessels / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D002417:Cattle; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D055370:Lung Injury / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018994:Myosin Light Chains / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010769:Phosphothreonine / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide; D015703:Antigens, CD; D015820:Cadherins; D008070:Lipopolysaccharides; D018994:Myosin Light Chains; D010749:Phosphoprotein Phosphatases; D010769:Phosphothreonine; D000071636:Protein Phosphatase 2C; D017346:Protein Serine-Threonine Kinases; D012265:Ribonucleotides; D020764:cdc42 GTP-Binding Protein; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein; D000099152:Cadherin 5; C109790:STK11 protein, human; C031143:AICA ribonucleotide