Histone deacetylase 7 controls endothelial cell growth through modulation of beta-catenin

Andriana Margariti, Anna Zampetaki, Qingzhong Xiao, Boda Zhou, Eirini Karamariti, Daniel Martin, Xiaoke Yin, Manuel Mayr, Hongling Li, Zhongyi Zhang, Elena De Falco, Yanhua Hu, Gillian Cockerill, Qingbo Xu, Lingfang Zeng

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84 Citations (Scopus)

Abstract

Rationale: Histone deacetylase (HDAC)7 is expressed in the early stages of embryonic development and may play a role in endothelial function.

Objective: This study aimed to investigate the role of HDAC7 in endothelial cell (EC) proliferation and growth and the underlying mechanism.

Methods and Results: Overexpression of HDAC7 by adenoviral gene transfer suppressed human umbilical vein endothelial cell (HUVEC) proliferation by preventing nuclear translocation of ß-catenin and downregulation of T-cell factor-1/Id2 (inhibitor of DNA binding 2) and cyclin D1, leading to G1 phase elongation. Further assays with the TOPFLASH reporter and quantitative RT-PCR for other ß-catenin target genes such as Axin2 confirmed that overexpression of HDAC7 decreased ß-catenin activity. Knockdown of HDAC7 by lentiviral short hairpin RNA transfer induced ß-catenin nuclear translocation but downregulated cyclin D1, cyclin E1 and E2F2, causing HUVEC hypertrophy. Immunoprecipitation assay and mass spectrometry analysis revealed that HDAC7 directly binds to ß-catenin and forms a complex with 14-3-3 e, ?, and ? proteins. Vascular endothelial growth factor treatment induced HDAC7 degradation via PLC?-IP3K (phospholipase C?–inositol-1,4,5-trisphosphate kinase) signal pathway and partially rescued HDAC7-mediated suppression of proliferation. Moreover, vascular endothelial growth factor stimulation suppressed the binding of HDAC7 with ß-catenin, disrupting the complex and releasing ß-catenin to translocate into the nucleus.

Conclusions: These findings demonstrate that HDAC7 interacts with ß-catenin keeping ECs in a low proliferation stage and provides a novel insight into the mechanism of HDAC7-mediated signal pathways leading to endothelial growth
Original languageEnglish
Article number2nd
Pages (from-to)1202-11
Number of pages10
JournalCirculation Research
Volume106
Issue number7
DOIs
Publication statusPublished - 2010

Bibliographical note

Accompanied by an Editorial: 106:1180-1183; A figure selected as the cover picture.

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