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Page 2 of 9 Kovacs et al. Vessel Plus 2018;2:15 I http://dx.doi.org/10.20517/2574-1209.2018.06
[3]
significant morbidity and frequently in death . To date no pharmacological therapies have been proven to
[4]
improve ALI in clinical trials . Approaches remain non-specific and rely on supportive care and control of
[5]
initial causes . A major pathophysiological alteration of ALI is the dysfunction of the pulmonary vascular
[6,7]
endothelial barrier resulting in pulmonary infiltrates, hypoxemia and pulmonary edema . Endothelial cells
(ECs) line the lumen of the blood vessels serving every organ system and provide a semi-selective barrier
[8]
between the blood and the interstitial space . In ALI, the EC barrier is compromised leading to elevated
[9]
vascular permeability . A lack of understanding the pathologic mechanisms involved in ALI remains an
obstacle to new and effective therapies that reduces the vascular leakage in ALI.

Recently, epigenetic mechanisms have gained great therapeutic potential in the treatment of inflammatory
and autoimmune diseases [10,11] . Previous studies have demonstrated that inflammatory gene expression is
regulated by the precise balance between histone-modulating enzymes; histone acetyltransferases (HATs)
and histone deacetylases (HDACs) [12,13] . In addition to modulating histone protein, it has been shown that
HDACs can also deacetylate many non-histone proteins to regulate cellular functions such as cytoskeletal
acetylation and polymerization, and signal transduction [14-16] . Acetylation of non-histone proteins might
[17]
crosstalk with other posttranslational modifications (PTMs) to control cellular signaling . HDACs are
classes of enzymes that catalyze the removal of the acetyl groups from specific lysine residues of the histone
[18]
or non-histone proteins . The inhibition of HDACs has been shown to play an important role in EC barrier
protection [19,20] . In this review, we intend to summarize the current knowledge focusing on the potential
effect of HDAC inhibition on the pathogenesis of the ALI.

CHARACTERIZATION OF HDACS
There are 18 characterized members of HDAC superfamily in human which can be divided into two
[21]
families and four classes according to their function and homology to yeast proteins [Table 1]. The
classical family includes the classes I, II, and IV HDACs which are zinc-dependent enzymes and perform
metal ion-mediated hydrolysis of acetamide bond in their acetylated substrates while silent information
regulator 2 (Sir2)-related protein (Sirtuin) family contains the class III HDACs requiring NAD+ as a cofactor
for enzymatic activity [22,23] . Mechanisms for HDAC regulation occurs at multiple levels involving protein
complex formation, PTMs such as phosphorylation, SUMOylation, subcellular localization, availability of
[24]
metabolic cofactors and proteolytic processing .

The class I HDACs (HDAC1, 2, 3, and 8) have sequence similarity to the yeast transcriptional regulator
reduced potassium dependency 3 (RPD3) protein. They are ubiquitously expressed and mainly localized
[25]
within the cellular nucleus . HDAC1 and HDAC2 contain nuclear localization signal (NLS), but not
[26]
nuclear export signal (NES), therefore they are restricted to the nucleus . HDAC3 are able to shuttle
between the nucleus and the cytoplasm which is regulated by competing nuclear import and nuclear export
[28]
[27]
signals . HDAC8 shows relatively low expression and can be found in the nucleus and in the cytoplasm .
Class I HDACs are ~350-500 amino acids long. They consist of the conserved deacetylase domain (DAC)
with short amino- and carboxy-terminal tails, latter can be modified by PTMs including phosphorylation or
[24]
SUMOylation in order to regulate the enzymatic activity . HDACs 1-3 form multiprotein complexes with
transcription factors and co-repressors to fulfil their deacetylase activities. HDAC8 does not form complexes
and is fully active in single molecule [29,30] .

The class II HDACs are protein orthologous to the yeast histone deacetylase-A 1 (HDA1) protein and can be
[25]
divided into two subclasses such as class IIa (HDAC4, 5, 7 and 9) and class IIb (HDAC6 and 10) . Class II
[31]
HDACs show tissue-specific expression pattern and functions . They are able to shuttle between nucleus
[32]
and cytoplasm, however, HDAC6 and 10 are predominantly localized in the cytoplasm . Class II HDACs
are considerably larger molecules than class I HDACs, and they have approximately 700-1200 amino acid