title: N-cadherin coordinates AMP kinase-mediated lung vascular repair.
abstract: Injury to the pulmonary circulation compromises endothelial barrier function and increases lung edema. Resolution of lung damage involves restoring barrier integrity, a process requiring reestablishment of endothelial cell-cell adhesions. However, mechanisms underlying repair in lung endothelium are poorly understood. In pulmonary microvascular endothelium, AMP kinase α1 (AMPKα1) stimulation enhances recovery of the endothelial barrier after LPS-induced vascular damage. AMPKα1 colocalizes to a discrete membrane compartment with the adhesion protein neuronal cadherin (N-cadherin). This study sought to determine N-cadherin's role in the repair process. Short-hairpin RNA against full-length N-cadherin or a C-terminally truncated N-cadherin, designed to disrupt the cadherin's interactions with intracellular proteins, were expressed in lung endothelium. Disruption of N-cadherin's intracellular domain caused translocation of AMPK away from the membrane and attenuated AMPK-mediated restoration of barrier function in LPS-treated endothelium. AMPK activity measurements indicated that lower basal AMPK activity in cells expressing the truncated N-cadherin compared with controls. Moreover, the AMPK stimulator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) failed to increase AMPK activity in cells expressing the modified N-cadherin, indicating uncoupling of a functional association between AMPK and the cadherin. Isolated lung studies confirmed a physiologic role for this pathway in vivo. AMPK activation reversed LPS-induced increase in permeability, whereas N-cadherin inhibition hindered AMPK-mediated repair. Thus N-cadherin coordinates the vascular protective actions of AMPK through a functional link with the kinase. This study provides insight into intrinsic repair mechanisms in the lung and supports AMPK stimulation as a modality for treating vascular disease.
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine, Center for Lung Injury and Repair.
authors.forename: Ming-Yuan
authors.initials: MY
authors.lastname: Jian
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Pediatric Neonatology, and.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Division of Molecular and Translational Biomedicine.
authors.forename: Paul
authors.initials: P
authors.lastname: Wolkowicz
authors.affiliation: Department of Physiology and Cell Biology, Center for Lung Biology, University of South Alabama, Mobile.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Alexeyev
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Zmijewski
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine, Center for Lung Injury and Repair, jcreighton@uab.edu.
authors.forename: Judy
authors.initials: J
authors.lastname: Creighton
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D004789:Enzyme Activation / Q000276:immunology; D008168:Lung / Q000098:blood supply* / Q000378:metabolism; D008297:Male; D017207:Rats, Sprague-Dawley; D012265:Ribonucleotides / Q000378:metabolism
chemical_list: D015820:Cadherins; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D000263:Adenylate Kinase; C031143:AICA ribonucleotide
keywords: adhesion; edema; endothelium; permeability; pulmonary