Uchl1, a deubiquitinating enzyme, regulates lung endothelial cell permeability in vitro and in vivo

Sumegha Mitra, Yulia Epshtein, Saad Sammani, Hector Quijada, Weiguo Chen, Mounica Bandela, Ankit A. Desai, Joe G.N. Garcia, Jeffrey R. Jacobson

Research output: Contribution to journalArticlepeer-review

Abstract

Increasing 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.

Original languageEnglish (US)
Pages (from-to)L497-L507
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume320
Issue number4
DOIs
StatePublished - 2021

Keywords

  • Adherens junction
  • Claudin-5
  • Endothelial cells
  • Lung vascular permeability
  • Tight junction
  • UCHL1
  • VE-cadherin

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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