title: Histone deacetylase 5 interacts with Krüppel-like factor 2 and inhibits its transcriptional activity in endothelium.
abstract: OBJECTIVE
  Vascular endothelial dysfunction and inflammation are hallmarks of atherosclerosis. Krüppel-like factor 2 (KLF2) is a key mediator of anti-inflammatory and anti-atherosclerotic properties of the endothelium. However, little is known of the molecular mechanisms for regulating KLF2 transcriptional activation.
  
  
  RESULTS
  Here, we found that histone deacetylase 5 (HDAC5) associates with KLF2 and represses KLF2 transcriptional activation. HDAC5 resided with KLF2 in the nuclei of human umbilical cord vein endothelial cells (HUVECs). Steady laminar flow attenuated the association of HDAC5 with KLF2 via stimulating HDAC5 phosphorylation-dependent nuclear export in HUVEC. We also mapped the KLF2-HDAC5-interacting domains and found that the N-terminal region of HDAC5 interacts with the C-terminal domain of KLF2. Chromatin immunoprecipitation and luciferase reporter assays showed that HDAC5 through a direct association with KLF2 suppressed KLF2 transcriptional activation. HDAC5 overexpression inhibited KLF2-dependent endothelial nitric oxide synthesis (eNOS) promoter activity in COS7 cell and gene expression in both HUVECs and bovine aortic endothelial cells (BAECs). Conversely, HDAC5 silencing enhanced KLF2 transcription and hence eNOS expression in HUVEC. Moreover, we observed that the level of eNOS protein in the thoracic aorta isolated from HDAC5 knockout mice was higher, whereas expression of pro-inflammatory vascular cell adhesion molecule 1 was lower, compared with those of HDAC5 wild-type mice.
  
  
  CONCLUSIONS
  We reveal a novel role of HDAC5 in modulating the KLF2 transcriptional activation and eNOS expression. These findings suggest that HDAC5, a binding partner and modulator of KLF2, could be a new therapeutic target to prevent vascular endothelial dysfunction associated with cardiovascular diseases.
authors.affiliation: Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box CVRI, Rochester, NY 14620, USA.
authors.forename: Il-Sun
authors.initials: IS
authors.lastname: Kwon
authors.affiliation: Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box CVRI, Rochester, NY 14620, USA.
authors.forename: Weiye
authors.initials: W
authors.lastname: Wang
authors.affiliation: Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box CVRI, Rochester, NY 14620, USA.
authors.forename: Suowen
authors.initials: S
authors.lastname: Xu
authors.affiliation: Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box CVRI, Rochester, NY 14620, USA zheng-gen_jin@urmc.rochester.edu.
authors.forename: Zheng-Gen
authors.initials: ZG
authors.lastname: Jin
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D019556:COS Cells; D002417:Cattle; D002522:Chlorocebus aethiops; D015971:Gene Expression Regulation, Enzymologic; D006655:Histone Deacetylases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D013314:Stress, Mechanical; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: C096161:KLF2 protein, human; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C404500:HDAC5 protein, human; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases
keywords: Endothelial cells; HDAC5; KLF2; Transcriptional activation; eNOS
references.citation: Blood. 2002 Sep 1;100(5):1689-98
references.pmid: 12176889
references.citation: Am J Physiol Renal Physiol. 2001 Feb;280(2):F193-206
references.pmid: 11208594
references.citation: Blood. 2010 Apr 8;115(14):2971-9
references.pmid: 20042720
references.citation: J Clin Invest. 2006 Jan;116(1):49-58
references.pmid: 16341264
references.citation: Mol Cell Biol. 2004 Oct;24(19):8374-85
references.pmid: 15367659
references.citation: Am J Pathol. 2005 Aug;167(2):609-18
references.pmid: 16049344
references.citation: J Biol Chem. 2006 Jun 2;281(22):15121-8
references.pmid: 16571724
references.citation: Development. 1999 May;126(10):2045-52
references.pmid: 10207130
references.citation: Int J Dev Biol. 2009;53(2-3):291-301
references.pmid: 19412888
references.citation: Physiol Genomics. 2000 Mar 13;2(2):77-83
references.pmid: 11015585
references.citation: J Biol Chem. 1995 Jun 23;270(25):15320-6
references.pmid: 7541039
references.citation: Circ Res. 2010 Apr 16;106(7):1202-11
references.pmid: 20224040
references.citation: Dev Biol. 1999 Jul 15;211(2):255-67
references.pmid: 10395786
references.citation: J Exp Med. 2004 May 17;199(10):1305-15
references.pmid: 15136591
references.citation: J Biol Chem. 2005 Jun 17;280(24):23371-9
references.pmid: 15834135
references.citation: Blood. 2009 May 28;113(22):5669-79
references.pmid: 19351956
references.citation: Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7738-43
references.pmid: 18509061
references.citation: Trends Biochem Sci. 2002 Jan;27(1):40-7
references.pmid: 11796223
references.citation: Ann N Y Acad Sci. 2000 May;902:230-9; discussion 239-40
references.pmid: 10865843
references.citation: Mol Cell Biol. 2005 Jul;25(14):5893-903
references.pmid: 15988006
references.citation: J Biol Chem. 2001 Sep 14;276(37):34355-8
references.pmid: 11443140
references.citation: Mol Cell Biol. 2004 Oct;24(19):8467-76
references.pmid: 15367668
references.citation: Circ Res. 2003 Aug 22;93(4):354-63
references.pmid: 12893742
references.citation: Genomics. 1994 Jan 15;19(2):350-7
references.pmid: 7514568
references.citation: Ann N Y Acad Sci. 2001 Dec;947:93-109; discussion 109-11
references.pmid: 11795313
references.citation: J Biol Chem. 2005 Sep 30;280(39):33262-9
references.pmid: 16006559
references.citation: Circ Res. 2007 Dec 7;101(12):1237-46
references.pmid: 17947801
references.citation: J Biol Chem. 2005 Apr 1;280(13):12305-9
references.pmid: 15665327
references.citation: Clin Cardiol. 1997 Nov;20(11 Suppl 2):II-3-10
references.pmid: 9422846
references.citation: Curr Opin Lipidol. 2001 Aug;12(4):383-9
references.pmid: 11507322
references.citation: Cardiovasc Res. 2007 Mar 1;73(4):667-77
references.pmid: 17217938
references.citation: Mol Cell. 2000 Aug;6(2):233-44
references.pmid: 10983972