Zinc-Dependent Histone Deacetylases in Lung Endothelial Pathobiology

Abstract

A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and, as such, provides a semi-selective barrier between the blood and the interstitial space. Compromise of the lung EC barrier due to inflammatory or toxic events may result in pulmonary edema, which is a cardinal feature of acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS). The EC functions are controlled, at least in part, via epigenetic mechanisms mediated by histone deacetylases (HDACs). Zinc-dependent HDACs represent the largest group of HDACs and are activated by Zn²⁺. Members of this HDAC group are involved in epigenetic regulation primarily by modifying the structure of chromatin upon removal of acetyl groups from histones. In addition, they can deacetylate many non-histone histone proteins, including those located in extranuclear compartments. Recently, the therapeutic potential of inhibiting zinc-dependent HDACs for EC barrier preservation has gained momentum. However, the role of specific HDAC subtypes in EC barrier regulation remains largely unknown. This review aims to provide an update on the role of zinc-dependent HDACs in endothelial dysfunction and its related diseases. We will broadly focus on biological contributions, signaling pathways and transcriptional roles of HDACs in endothelial pathobiology associated mainly with lung diseases, and we will discuss the potential of their inhibitors for lung injury prevention.

Keywords: HDAC inhibitors; acute lung injury; acute respiratory distress syndrome; deacetylation; endothelial barrier integrity; lung vascular endothelium; zinc-dependent HDACs.

Figure 1

The schematic illustrates enzymes responsible for reversible protein acetylation in the regulation of gene transcription. Two classes of regulatory enzymes, lysine acetyltransferases (KATs)/histone acetyltransferases (HATs) and lysine deacetylases (KDACs)/histone deacetylases (HDACs), govern the reversible post-translational Nε acetylation of Lys residues in proteins. While KATs/HATs facilitate the addition of acetyl group to Lys residues and promote chromatin unfolding (relaxed chromatin), thus facilitating the activation of transcription, KDACs/HDACs catalyze acetyl group removal from histone and non-histone targets and are responsible for chromatin condensation (repression of transcription).

Figure 2

Structural features of zinc-dependent HDACs. The schematic depicts the main structural peculiarities of zinc-dependent HDACs. See the text for further explanation. Additional information on HDACs secondary and tertiary structures is provided in Supplementary Figure S1.

Figure 3

Main endothelial signaling pathways mediated by zinc-dependent HDACs. HDAC1, HDAC3, and HDAC6 are involved in apoptosis. HDAC1, HDAC6, and HDAC8 are responsible for vascular tone. HDAC3 and HDAC6 control cell differentiation. HDACs 1 to 7 participate in cell proliferation. Except for HDAC8, HDAC10, and HDAC11, all other zinc-dependent HDACs drive angiogenesis. HDAC1, HDAC2, HDAC3, HDAC5, and HDAC6 regulate NO production. Aside from HDAC4 and HDAC10, the rest of the zinc-dependent HDACs are involved in inflammatory responses. HDACs 3 to 7 and HDAC11 are the key players accounting for the regulation of cell integrity. HDAC2, HDAC3, and HDAC6 are contributors to oxidative stress. See the text for further explanations and references.

Figure 4

Zinc-dependent HDACs and their inhibitors. This figure (made at SankeyMATIC.com) illustrates four distinct classes of HDAC inhibitors: aliphatic acids, hydroxamate, benzamide, and cyclic peptide. Among these, trichostatin A (TSA), belinostat, panobinostat, and vorinostat are hydroxamate inhibitors, with TSA being the most extensively studied. Depsipeptide falls within the cyclic peptide class. Notably, the inhibitors MS-275 (etinostat) and MGCD0103 (mocetinostat) target HDAC1, HDAC2, HDAC3, and HDAC8, classified as class I HDACs, and are categorized as benzamides. Aliphatic acids encompass 4-phenylbutyric acid (phenyl butyrate), sodium butyrate (sodium salt of butyric acid), and valproic acid (valproate).