UCHL1, a deubiquitinating enzyme, regulates lung endothelial cell permeability in vitro and in vivo
Desai, Ankit A
Garcia, Joe G N
Jacobson, Jeffrey R
AffiliationDepartment of Medicine, Arizona Health Sciences Center, University of Arizona
lung vascular permeability
MetadataShow full item record
PublisherAmerican Physiological Society
CitationMitra, S., Epshtein, Y., Sammani, S., Quijada, H., Chen, W., Bandela, M., ... & Jacobson, J. R. (2021). UCHL1, a deubiquitinating enzyme, regulates lung endothelial cell permeability in vitro and in vivo. American Journal of Physiology-Lung Cellular and Molecular Physiology, 320(4), L497-L507.
RightsCopyright © 2021 the American Physiological Society.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractIncreasing evidence suggests an important role for deubiquitinating enzymes (DUBs) in modulating a variety of biological functions and diseases. We previously identified the upregulation of the DUB ubiquitin carboxyl terminal hydrolase 1 (UCHL1) in murine ventilator-induced lung injury (VILI). However, the role of UCHL1 in modulating vascular permeability, a cardinal feature of acute lung injury (ALI) in general, remains unclear. We investigated the role of UCHL1 in pulmonary endothelial cell (EC) barrier function in vitro and in vivo and examined the effects of UCHL1 on VE-cadherin and claudin-5 regulation, important adherens and tight junctional components, respectively. Measurements of transendothelial electrical resistance confirmed decreased barrier enhancement induced by hepatocyte growth factor (HGF) and increased thrombin-induced permeability in both UCHL1-silenced ECs and in ECs pretreated with LDN-57444 (LDN), a pharmacological UCHL1 inhibitor. In addition, UCHL1 knockdown (siRNA) was associated with decreased expression of VE-cadherin and claudin-5, whereas silencing of the transcription factor FoxO1 restored claudin-5 levels. Finally, UCHL1 inhibition in vivo via LDN was associated with increased VILI in a murine model. These findings support a prominent functional role of UCHL1 in regulating lung vascular permeability via alterations in adherens and tight junctions and implicate UCHL1 as an important mediator of ALI.
Note12 month embargo; published online 31 March 2021
VersionFinal accepted manuscript
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