Microtubules mediate anti-inflammatory and lung vascular barrier protective effects of atrial natriuretic peptide

Independently on control of circulating fluid, atrial natriuretic peptide (ANP) exhibits anti-inflammatory effects in the lung. We tested a role of microtubule (MT) cytoskeleton in the ANP-induced protection against endothelial cell (EC) barrier dysfunction and acute lung injury induced by Staphylococcus aureus-derived peptidoglican-G (PepG). ANP attenuated PepG-induced Rho signaling via suppression of PepG-induced MT disassembly and inhibition of MT-associated Rho-specific guanine nucleotide exchange factor GEF-H1. ANP-induced EC barrier preservation and MT stabilization was due to phosphorylation and inactivation of MT-associated protein stathmin. Phosphorylation deficient stathmin-S63A mutant abolished ANP protective effects against PepG-induced hyperpermeability, activation of Rho and NFkB signaling, and expression of inflammatory adhesion molecules. In contrast, siRNA-based stathmin knockdown prevented PepG-induced peripheral MT disassembly and EC barrier dysfunction. ANP protective effects in murine model of PepG-induced lung injury were associated with increased acetylated MT and phospho-stathmin levels, 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 ANP knockout mice. These results show a novel mechanism of EC barrier protection and mitigation of inflammation by ANP in EC culture and in the in vivo model of lung injury via stathmin-dependent MT as...
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: 3.3 Mechanisms of Lung Injury and Repair Source Type: research