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Page 4 of 9 Kovacs et al. Vessel Plus 2018;2:15 I http://dx.doi.org/10.20517/2574-1209.2018.06

modify chromatin structure and the activity of transcription factors that serve as an important mechanism
[43]
for the regulation of gene expression . Deacetylation of histones by HDACs contributes to the compaction
[44]
of the chromatin structure correlating with gene silencing . Genome-wide mapping revealed that HDACs
are also associated with active genes and positively correlated with gene transcription, indicating that
they do not only remove the acetyl group in active genes but also reset the chromatin for activation of
[45]
gene transcription . HDACs deacetylate transcriptional factors mostly repressing the gene expression.
However, HDACs can also activate transcription by either reducing the transcription of transcriptional
repressor proteins or by deacetylating and activating the transcription activators or by deacetylating and
[21]
inhibiting the transcription repressors . In addition to regulation of gene expression, activities of HDACs
have been shown to indirectly regulate other PTMs including phosphorylation, ubiquitination, methylation,
[17]
SUMOylation, NEDDilation, biotinylation, etc. . Lysine acetylation can interfere with other lysine
modifications, conversely, removal of the acetyl group can promote other lysine modifications that control
vital cellular functions such as mRNA integrity, translation, enzymatic activity as well as protein stability,
[46]
function, localization and interactions . For example, there is a direct competition between acetylation and
ubiquitination, namely acetylation blocks ubiquitination and proteasome-mediated degradation of target
[47]
proteins. Similarly, the deacetylation facilitates protein degradation . Members of the HDAC superfamily
have been shown to be involved in many physiological processes such as cell migration, proliferation and
survival, cell differentiation, cell cycle, signal transduction, aging, DNA repair and apoptosis [48,49] . Growing
body of evidence show that malfunction of the HDACs play a critical role in many human disorders
including cancer, neurodegenerative diseases, metabolic and immunological disorders, inflammatory,
cardiac and pulmonary diseases [50,51] . HDAC inhibition has been reported to display antitumor and anti-
inflammation properties [52-55] . It has also been shown that HDACs play an important role in various
inflammatory lung diseases including ALI, COPD, and asthma [56-58] .

HDACS IN ALI
Several reports have indicated that HDAC inhibitors possess beneficial effect in ALI animal models.
The primary causes of ALI are the endothelial barrier dysfunction and inflammation [59,60] . It has been
[19]
shown that HDAC6-specific inhibitor tubacin ameliorates pulmonary edema in the LPS-induced ALI .
Pharmacological inhibition of HDAC6 suppresses the thrombin-induced endothelial barrier dysfunction
[61]
[19]
through increased acetylation of α-tubulin and microtubules stabilization . In addition, Yu et al.
found that selective inhibition of HDAC6 by tubastatin A (Tub A) blocks TNF-α-induced lung endothelial
permeability and prevents endotoxin-induced pulmonary edema. Pretreatment with Tub A enhanced
α-tubulin acetylation and decreased the TNF-α-induced microtubule disassembly, endothelial cell
contraction and actin stress fiber formation as well as reduced the phosphorylation of the myosin light chain
[61]
attenuating the lung endothelial cell hyperpermeability caused by the cytokine . In addition, HDAC6
inhibition by Tub A increases β-catenin acetylation and consequently its membrane translocation leading
[61]
to increased stabilization of adherens junctions in endothelial cells . Moreover, inhibition of HDAC6
prevents endotoxin-induced deacetylation of α-tubulin and β-catenin in lung tissues and attenuates lung
[61]
edema formation in mouse model of endotoxemia . The same group demonstrated that selective inhibitors
of HDAC6 such as CAY10603 and Tub A prevented the TNF-α-induced caspase 3 activation and endothelial
[62]
barrier dysfunction via maintaining cell-cell junction integrity . In addition, inhibition of HDAC6 by
CAY10603 alleviated the endotoxin-induced lung vascular permeability and caspase-3 activation as well as
[62]
[20]
reduced the lung edema formation . Joshi et al. revealed the mediating role of HDACs in LPS-induced
endothelial hyperpermeability and ALI. Inhibition of various HDACs by pan-HDAC inhibitors including
panobinostat or trichostatin (TSA) attenuates LPS-induced decrease in transendothelial electrical resistance
(TER), Hsp90 activation and chaperone function as wells as diminishes the RhoA activity and signaling.
Moreover, pre-treatment with HDAC3-selective inhibitor RGFP-966 or with HDAC6- selective inhibitor Tub