title: Cystathionine γ-lyase protects vascular endothelium: a role for inhibition of histone deacetylase 6.
abstract: Endothelial cystathionine γ-lyase (CSEγ) contributes to cardiovascular homeostasis, mainly through production of H2S. However, the molecular mechanisms that control CSEγ gene expression in the endothelium during cardiovascular diseases are unclear. The aim of the current study is to determine the role of specific histone deacetylases (HDACs) in the regulation of endothelial CSEγ. Reduced CSEγ mRNA expression and protein abundance were observed in human aortic endothelial cells (HAEC) exposed to oxidized LDL (OxLDL) and in aortas from atherogenic apolipoprotein E knockout (ApoE-/-) mice fed a high-fat diet compared with controls. Intact murine aortic rings exposed to OxLDL (50 μg/ml) for 24 h exhibited impaired endothelium-dependent vasorelaxation that was blocked by CSEγ overexpression or the H2S donor NaHS. CSEγ expression was upregulated by pan-HDAC inhibitors and by class II-specific HDAC inhibitors, but not by other class-specific inhibitors. The HDAC6 selective inhibitor tubacin and HDAC6-specific siRNA increased CSEγ expression and blocked OxLDL-mediated reductions in endothelial CSEγ expression and CSEγ promoter activity, indicating that HDAC6 is a specific regulator of CSEγ expression. Consistent with this finding, HDAC6 mRNA, protein expression, and activity were upregulated in OxLDL-exposed HAEC, but not in human aortic smooth muscle cells. HDAC6 protein levels in aortas from high-fat diet-fed ApoE-/-mice were comparable to those in controls, whereas HDAC6 activity was robustly upregulated. Together, our findings indicate that HDAC6 is upregulated by atherogenic stimuli via posttranslational modifications and is a critical regulator of CSEγ expression in vascular endothelium. Inhibition of HDAC6 activity may improve endothelial function and prevent or reverse the development of atherosclerosis.NEW & NOTEWORTHYOxidative injury to endothelial cells by oxidized LDL reduced cystathionine γ-lyase (CSEγ) expression and H2S production, leading to endothelial dysfunction, which was prevented by histone deacetylase 6 (HDAC6) inhibition. Our data suggest HDAC6 as a novel therapeutic target to prevent the development of atherosclerosis.
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Thorsten M
authors.initials: TM
authors.lastname: Leucker
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Nomura
authors.affiliation: Department of Anesthesiology and Pain Medicine, Ajou University School of Medicine, Suwon, South Korea.
authors.forename: Jae Hyung
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Anil
authors.initials: A
authors.lastname: Bhatta
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Victor
authors.initials: V
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wecker
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Jandu
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Santhanam
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Dan
authors.initials: D
authors.lastname: Berkowitz
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Lewis
authors.initials: L
authors.lastname: Romer
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; dpandey2@jhmi.edu.
authors.forename: Deepesh
authors.initials: D
authors.lastname: Pandey
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D003542:Cystathionine gamma-Lyase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology*; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D056572:Histone Deacetylase Inhibitors; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide
keywords: CSEγ; H2S; HDAC6; OxLDL; atherosclerosis; endothelial function; transcriptional regulation