title: Selective HDAC6 inhibition prevents TNF-α-induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema.
abstract: Lung endothelial damage contributes to the pathogenesis of acute lung injury. New strategies against lung endothelial barrier dysfunction may provide therapeutic benefits against lung vascular injury. Cell-cell junctions and microtubule cytoskeleton are basic components in maintaining endothelial barrier integrity. HDAC6, a deacetylase primarily localized in the cytoplasm, has been reported to modulate nonnuclear protein function through deacetylation. Both α-tubulin and β-catenin are substrates for HDAC6. Here, we examined the effects of tubastatin A, a highly selective HDAC6 inhibitor, on TNF-α induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema. Selective HDAC6 inhibition by tubastatin A blocked TNF-α-induced lung endothelial cell hyperpermeability, which was associated with increased α-tubulin acetylation and microtubule stability. Tubastatin A pretreatment inhibited TNF-α-induced endothelial cell contraction and actin stress fiber formation with reduced myosin light chain phosphorylation. Selective HDAC6 inhibition by tubastatin A also induced β-catenin acetylation in human lung endothelial cells, which was associated with increased membrane localization of β-catenin and stabilization of adherens junctions. HDAC6 knockdown by small interfering RNA also prevented TNF-α-induced barrier dysfunction and increased α-tubulin and β-catenin acetylation in endothelial cells. Furthermore, in a mouse model of endotoxemia, tubastatin A was able to prevent endotoxin-induced deacetylation of α-tubulin and β-catenin in lung tissues, which was associated with reduced pulmonary edema. Collectively, our data indicate that selective HDAC6 inhibition by tubastatin A is a potent approach against lung endothelial barrier dysfunction.
authors.affiliation: The Second Hospital of Jilin University, Jilin, China; Center for Research on Environmental Disease, College of Medicine, University of Kentucky, Lexington, Kentucky; Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, Kentucky; and.
authors.forename: Jinyan
authors.initials: J
authors.lastname: Yu
authors.affiliation: The Second Hospital of Jilin University, Jilin, China;
authors.forename: Zhongsen
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Center for Biomedical Research, University of Texas Health Science Center, Tyler, Texas.
authors.forename: Sreerama
authors.initials: S
authors.lastname: Shetty
authors.affiliation: The Second Hospital of Jilin University, Jilin, China; Center for Research on Environmental Disease, College of Medicine, University of Kentucky, Lexington, Kentucky;
authors.forename: Mengshi
authors.initials: M
authors.lastname: Ma
authors.affiliation: Center for Research on Environmental Disease, College of Medicine, University of Kentucky, Lexington, Kentucky; Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, Kentucky; and jian.fu@uky.edu.
authors.forename: Jian
authors.initials: J
authors.lastname: Fu
mesh_terms: D000107:Acetylation; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000378:metabolism; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D011654:Pulmonary Edema / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D014404:Tubulin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D008070:Lipopolysaccharides; D014404:Tubulin; D014409:Tumor Necrosis Factor-alpha; C553587:tubastatin A; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: HDAC6; catenin; endothelial barrier; lung injury; tubulin