Histone deacetylases in vascular permeability and remodeling associated with acute lung injury

Abstract

Acute lung injury (ALI) is a severe progressive disorder that arises from a wide range of causes such as toxins or inflammation, resulting in significant morbidity and mortality. There are no effective therapeutic options apart from mechanical ventilation strategies. While the mechanisms that govern the clinically relevant process of increased EC permeability and remodeling associated with ALI are under intense investigation, our knowledge of the processes that determine barrier enhancement or preservation are far from completion. Recently, epigenetic mechanisms have emerged as a major regulator of enduring changes in cell behavior and the therapeutic potential of inhibiting histone deacetylases (HDACs) for the treatment of cardiovascular and inflammatory diseases has gained remarkable attention. Although HDACs have been shown to play an important role in regulating EC barrier function, the involved HDAC subtypes and mechanisms remain undefined. Further investigation of the HDAC signaling may provide therapeutic approaches for the prevention and treatment of ALI.

Keywords: acute lung injury; endothelial barrier function; histone deacetylases.

Figure 1.

Schematic illustration of role of HDACs in Acute Lung Injury. HDAC inhibitors: Tubacin (N1-[4-[(2R,4R,6S)-4-[[(4,5-diphenyl-2-oxazolyl)thio]methyl]-6-[4-(hydroxymethyl)phenyl]-1,3-dioxan-2-yl]phenyl]-N8-hydroxy-octanediamide) ^[19,70]; Panobinostat (NVP-LBH589) ^[20]; Trichostatin A (TSA, 7-[4-(dimethylamino)phenyl]-N-hydroxy-4,6R-dimethyl-7-oxo-2E,4E-heptadienamide) ^{[20, 64]}; RGFP-966 ((2E)-N-(2-Amino-4-fluorophenyl)-3-[(2E)-1-(3-phenyl-2-propen-1-yl)-1H-pyrazol-4-yl]-2-propenamide) ^[20]; Tubastatin A (N-hydroxy-4-[(1,2,3,4-tetrahydro-2-methyl-5H-pyrido[4,3-b]indol-5-yl)methyl]-benzamide) ^[61,62]; CAY10603 (N-[4-[3-[[[7-(hydroxyamino)-7-oxoheptyl]amino]carbonyl]-5-isoxazolyl]phenyl]-1,1-dimethylethyl ester, carbamic acid) ^[61,62]; Sodium Butyrate (butanoic acid sodium salt) ^[63,64]; Valproic acid (VPA, 2-Propylpentanoic acid) ^{[65,66, 67]}; Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) ^[68]. Abbreviations: LPS - lipopolysaccharides; E.coli - Escherichia coli; I/R - ischemia-reperfusion; MLC - myosin light chain; TNF-α - Tumor necrosis factor- α; CINC-1 - cytokine-induced neutrophil chemoattractant-1; IL-1β - Interleukin 1β; IL-6 - Interleukin 6; NO - nitric oxide; ICAM-1 - Intercellular Adhesion Molecule 1; NF- κB p65 - Nuclear factor NF-kappa-B p65 subunit; MPO - myeloperoxidase.