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Histone deacetylase (HDAC) inhibition prevents and restores bacterial lipopolysaccharide (LPS)‐induced paracellular hyper‐permeability in human lung microvascular endothelial cells (HLMVEC)
Author(s) -
Joshi Atul D,
Thangjam Gagan,
Barabutis Nektarios,
Shaw Mary,
Patel Vijay,
Catravas John D
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.647.12
Subject(s) - hsp90 , microbiology and biotechnology , endothelial stem cell , chemistry , lipopolysaccharide , barrier function , histone deacetylase , panobinostat , heat shock protein , biology , biochemistry , histone , immunology , in vitro , gene
Objective LPS disrupts the barrier function of endothelial cell monolayers and increases their permeability to proteins. We have previously shown that inhibition of hsp90 protects and restores LPS‐mediated hyperpermeability in human lung microvascular endothelial cells (HLMVEC). Inhibition of histone deacetylases (HDAC) hyperacetylates hsp90 and thus suppresses its chaperone function. In this study we investigated the effects of HDAC inhibition on LPS‐mediated endothelial barrier disruption. Methods Endothelial permeability was measured by electric cell‐substrate impedance sensing (ECIS), in HLMVEC grown to confluence on gold‐plated arrays. Results Pre‐treatment with the HDAC inhibitors (TSA, butyrate or panobinostat) protected HLMVEC monolayers from LPS‐mediated hyperpermeability. Treatment with either TSA (2μM) or panobinostat (1μM) 3–6 hours after LPS exposure, restored endothelial barrier function. In addition, LPS‐mediated phosphorylation of MLC and hsp27 was attenuated by pre‐treatment with TSA or panobinostat, possibly preventing cytoskeleton rearrangement. TSA also disrupted hsp90‐CDC37 interaction, in the presence or absence of LPS, indicating a loss of hsp90 chaperone function. Conclusion HDAC inhibition protects and restores LPS‐mediated endothelial barrier function possibly by inhibiting hsp90 chaperone function. (Supported by HL093460 and HL101902)