title: Role of microtubules in attenuation of PepG-induced vascular endothelial dysfunction by atrial natriuretic peptide.
abstract: Apart from control of circulating fluid, atrial natriuretic peptide (ANP) exhibits anti-inflammatory effects in the lung. However, molecular mechanisms of ANP anti-inflammatory effects are not well-understood. Peripheral microtubule (MT) dynamics is essential for agonist-induced regulation of vascular endothelial permeability. Here we studied the role of MT-dependent signaling in ANP protective effects against endothelial cell (EC) barrier dysfunction and acute lung injury induced by Staphylococcus aureus-derived peptidoglican-G (PepG). PepG-induced vascular endothelial dysfunction was accompanied by MT destabilization and disruption of MT network. ANP attenuated PepG-induced MT disassembly, NFκB signaling and activity of MT-associated Rho activator GEF-H1 leading to attenuation of EC inflammatory activation reflected by expression of adhesion molecules ICAM1 and VCAM1. ANP-induced EC barrier preservation and MT stabilization were linked to phosphorylation and inactivation of MT-depolymerizing protein stathmin. Expression of stathmin phosphorylation-deficient mutant abolished ANP protective effects against PepG-induced inflammation and EC permeability. In contrast, siRNA-mediated stathmin knockdown prevented PepG-induced peripheral MT disassembly and endothelial barrier dysfunction. ANP protective effects in a murine model of PepG-induced lung injury were associated with increased phosphorylation of stathmin, while exacerbated lung injury in the ANP knockout mice was accompanied by decreased pool of stable MT. Stathmin knockdown in vivo reversed exacerbation of lung injury in the ANP knockout mice. These results show a novel MT-mediated mechanism of endothelial barrier protection by ANP in pulmonary EC and animal model of PepG-induced lung injury via stathmin-dependent control of MT assembly.
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Isa
authors.initials: I
authors.lastname: Mambetsariev
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Nicolene
authors.initials: N
authors.lastname: Sarich
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Fanyong
authors.initials: F
authors.lastname: Meng
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. Electronic address: abirukov@medicine.bsd.uchicago.edu.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Birukova
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000502:physiology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000503:physiopathology*; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000502:physiology*; D010457:Peptidoglycan / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D050777:Stathmin / Q000235:genetics / Q000378:metabolism
chemical_list: D010457:Peptidoglycan; D050777:Stathmin; D009320:Atrial Natriuretic Factor
keywords: Cytoskeleton; Endothelium; Lung injury; Permeability; Vascular leak