title: Histone deacetylase 3 is critical in endothelial survival and atherosclerosis development in response to disturbed flow.
abstract: BACKGROUND
  Histone deacetylase 3 (HDAC3) is known to play a crucial role in the differentiation of endothelial progenitors. The role of HDAC3 in mature endothelial cells, however, is not well understood. Here, we investigated the function of HDAC3 in preserving endothelial integrity in areas of disturbed blood flow, ie, bifurcation areas prone to atherosclerosis development.
  
  
  RESULTS
  En face staining of aortas from apolipoprotein E-knockout mice revealed increased expression of HDAC3, specifically in these branching areas in vivo, whereas rapid upregulation of HDAC3 protein was observed in endothelial cells exposed to disturbed flow in vitro. Interestingly, phosphorylation of HDAC3 at serine/threonine was observed in these cells, suggesting that disturbed flow leads to posttranscriptional modification and stabilization of the HDAC3 protein. Coimmunoprecipitation experiments showed that HDAC3 and Akt form a complex. Using a series of constructs harboring deletions, we found residues 136 to 206 of HDAC3 to be crucial in this interaction. Enforced expression of HDAC3 resulted in increased phosphorylation of Akt and upregulation of its kinase activity. In line with these findings, knockdown of HDAC3 with lentiviral vectors (shHDAC3) led to a dramatic decrease in cell survival accompanied by apoptosis in endothelial cells. In aortic isografts of apolipoprotein E-knockout mice treated with shHDAC3, a robust atherosclerotic lesion was formed. Surprisingly, 3 of the 8 mice that received shHDAC3-infected grafts died within 2 days after the operation. Miller staining of the isografts revealed disruption of the basement membrane and rupture of the vessel.
  
  
  CONCLUSIONS
  Our findings demonstrated that HDAC3 serves as an essential prosurvival molecule with a critical role in maintaining the endothelial integrity via Akt activation and that severe atherosclerosis and vessel rupture in isografted vessels of apolipoprotein E-knockout mice occur when HDAC3 is knocked down.
authors.affiliation: Cardiovascular Division, King's College London BHF Centre, London, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Zampetaki
authors.forename: Lingfang
authors.initials: L
authors.lastname: Zeng
authors.forename: Andriana
authors.initials: A
authors.lastname: Margariti
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Xiao
authors.forename: Hongling
authors.initials: H
authors.lastname: Li
authors.forename: Zhongyi
authors.initials: Z
authors.lastname: Zhang
authors.forename: Anna Elena
authors.initials: AE
authors.lastname: Pepe
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Ouassila
authors.initials: O
authors.lastname: Habi
authors.forename: Elena
authors.initials: E
authors.lastname: deFalco
authors.forename: Gillian
authors.initials: G
authors.lastname: Cockerill
authors.forename: Justin C
authors.initials: JC
authors.lastname: Mason
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Hu
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000637:transplantation; D001057:Apolipoproteins E / Q000235:genetics; D017209:Apoptosis / Q000502:physiology; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology* / Q000201:enzymology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007763:Lac Operon; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010766:Phosphorylation / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011673:Pulsatile Flow / Q000502:physiology; D014471:Umbilical Veins / Q000166:cytology; D000099186:Histone Deacetylase 3
chemical_list: D001057:Apolipoproteins E; D006655:Histone Deacetylases; D051057:Proto-Oncogene Proteins c-akt; D000099186:Histone Deacetylase 3