Role of histone deacetylases in transcription factor regulation and cell cycle modulation in endothelial cells in response to disturbed flow

Ding Yu Lee, Chih I. Lee, Ting Er Lin, Seh Hong Lim, Jing Zhou, Ying Chih Tseng, Shu Chien, Jeng Jiann Chiu

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

Vascular endothelial cells (ECs) are exposed to different flow patterns (i.e., disturbed vs. laminar), and the associated oscillatory shear stress (OSS) or pulsatile shear stress (PSS) lead to differential responses. We investigated the roles of class I and II histone deacetylases (HDAC-1/2/3 and HDAC-5/7, respectively) in regulating NF-E2-related factor-2 (Nrf2) and Krüppel-like factor-2 (KLF2), two transcription factors governing many shear-responsive genes, and the cell cycle in ECs in response to OSS. Application of OSS (0.5 ± 4 dynes/cm 2) to cultured ECs sustainably up-regulated class I and II HDACs and their nuclear accumulation, whereas PSS (12 ± 4 dynes/cm 2) induced phosphorylation-dependent nuclear export of class II HDACs. En face immunohistochemical examination of rat aortic arch and experimentally stenosed abdominal aorta revealed high HDAC-2/3/5 levels in ECs in areas exposed to disturbed flow. OSS induced the association of HDAC-1/2/3 with Nrf2 and HDAC-3/5/7 with myocyte enhancer factor-2; deacetylation of these factors led to down-regulation of antioxidant gene NAD(P)H quinone oxidoreductase-1 (NQO1) and KLF2. HDAC-1/2/3- and HDAC-3/5/7-specific small interfering RNAs eliminated the OSS-induced downregulation of NQO1 and KLF2, respectively. OSS up-regulated cyclin A and down-regulated p21 CIP1 in ECs and induced their proliferation; these effects were mediated by HDAC-1/2/3. Intraperitoneal administration of the class I-specific HDAC inhibitor valproic acid into bromodeoxyuridine (BrdU)-infused rats inhibited the increased EC uptake of BrdU at poststenotic sites. The OSS-induced HDAC signaling and EC responses are mediated by phosphatidylinositol 3-kinase/Akt. Our findings demonstrate the important roles of different groups of HDACs in regulating the oxidative, inflammatory, and proliferative responses of ECs to disturbed flow with OSS.

Original languageEnglish
Pages (from-to)1967-1972
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number6
DOIs
Publication statusPublished - Feb 7 2012
Externally publishedYes

Keywords

  • Epigenetics
  • Mechanotransduction
  • Transcriptional regulation

ASJC Scopus subject areas

  • General

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