Role of claudin-5 in the attenuation of murine acute lung injury by simvastatin.

TitleRole of claudin-5 in the attenuation of murine acute lung injury by simvastatin.
Publication TypeJournal Article
Year of Publication2014
AuthorsChen W, Sharma R, Rizzo AN, Siegler JH, Garcia JGN, Jacobson JR
JournalAm J Respir Cell Mol Biol
Volume50
Issue2
Pagination328-36
Date Published2014 Feb
ISSN Number1535-4989
KeywordsAcute Lung Injury, Animals, beta Catenin, Capillary Permeability, Cells, Cultured, Claudin-5, Disease Models, Animal, Endothelial Cells, Gene Expression Regulation, Gene Silencing, Humans, Lung, Mice, Mice, Inbred C57BL, Simvastatin, Tight Junctions
Abstract

<p>The statins are now recognized to have pleiotropic properties, including augmentation of endothelial barrier function. To explore the mechanisms involved, we investigated the effect of simvastatin on endothelial cell (EC) tight junctions. Western blotting of human pulmonary artery ECs treated with simvastatin (5 μM) confirmed a significant time-dependent increase (16-48 h) in claudin-5 protein expression compared with controls, without detectable alterations in zonula occludens-1 or occludin. These effects were associated with membrane translocation of VE-cadherin, whereas translocation of vascular endothelial cadherin (VE-cadherin; silencing RNA) inhibited simvastatin-induced claudin-5 up-regulation. Moreover, simvastatin treatment of ECs induced increased phosphorylation of both FoxO1 and β-catenin, transcriptional regulators of claudin-5 expression mediated by VE-cadherin. Subsequently, we found no effect of claudin-5 silencing on EC barrier protection by simvastatin in response to thrombin stimulation, as measured by either transendothelial electrical resistance or by EC monolayer flux of FITC-dextran (2,000 kD). However, silencing of claudin-5 did significantly attenuate simvastatin-mediated EC barrier protection in response to thrombin, as measured by monolayer flux of sodium fluorescein (376 Da). Finally, employing a murine model of LPS-induced acute lung injury, there was no effect of claudin-5 silencing in vivo (intratracheal injection) on bronchoalveolar lavage fluid protein or cell counts, but LPS-induced lung tissue extravasation of the small molecular weight markers, sodium fluorescein and Hochst stain (562 Da), were significantly increased in claudin-5-silenced animals compared with simvastatin-treated control animals. These findings implicate a distinct mechanism underlying size-selective endothelial barrier-protective properties of statins, and may ultimately lead to new novel therapeutic targets for patients with acute lung injury.</p>

DOI10.1165/rcmb.2013-0058OC
Alternate JournalAm. J. Respir. Cell Mol. Biol.
PubMed ID24028293
PubMed Central IDPMC3930946
Grant ListR01 HL096887 / HL / NHLBI NIH HHS / United States
HL096887 / HL / NHLBI NIH HHS / United States