Histone Deacetylase 7 Controls Endothelial Cell Growth Through Modulation of β-Catenin
Histone Deacetylase 7 Controls Endothelial Cell Growth Through Modulation of β-Catenin
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DOI：
10.1161/circresaha.109.213165
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发表时间：
2010-04-16
影响因子：
20.1
通讯作者：
Zeng, Lingfang
中科院分区：
文献类型：
--
作者：
Margariti, Andriana;Zampetaki, Anna;Zeng, Lingfang
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 beta-catenin and downregulation of T-cell factor-1/Id2 (inhibitor of DNA binding 2) and cyclin D1, leading to G(1) phase elongation. Further assays with the TOPFLASH reporter and quantitative RT-PCR for other beta-catenin target genes such as Axin2 confirmed that overexpression of HDAC7 decreased beta-catenin activity. Knockdown of HDAC7 by lentiviral short hairpin RNA transfer induced beta-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 beta-catenin and forms a complex with 14-3-3 epsilon, zeta, and eta proteins. Vascular endothelial growth factor treatment induced HDAC7 degradation via PLC gamma-IP3K (phospholipase C gamma-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 beta-catenin, disrupting the complex and releasing beta-catenin to translocate into the nucleus.Conclusions: These findings demonstrate that HDAC7 interacts with beta-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. (Circ Res. 2010;106:1202-1211.)
