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Role of histone deacetylases in regulation of NF‐E2‐related factor 2, kruppel‐like factor 2, and cell cycle in vascular endothelial cells in response to disturbed flow
Author(s) -
Chiu Jeng-Jiann,
Lee Ding-Yu,
Chien Shu
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1129.1
Subject(s) - klf2 , transcription factor , microbiology and biotechnology , mef2 , sirt6 , chemistry , cell cycle , acetylation , cancer research , biology , enhancer , cell , biochemistry , gene , sirtuin
Vascular endothelial cells (ECs) are exposed to different patterns of blood flow (disturbed vs . laminar) and the associated shear stresses (oscillatory [OSS] vs . pulsatile [PSS]), which lead to differential EC responses. We investigated the roles of classes I and II histone deacetylases (HDACs, i.e., HDAC‐1/2/3 and HDAC‐5/7, respectively) in regulating NF‐E2‐related factor‐2 (Nrf2) and Krüppel‐like factor‐2 (KLF2), two important transcription factors that govern many shear‐responsive genes, and cell cycle in ECs in response to OSS. Application of OSS (0.5±4 dynes/cm 2 ) to ECs up‐regulated both classes I and II HDACs and their nuclear accumulations, whereas PSS (12±4 dynes/cm 2 ) induced phosphorylation‐dependent nuclear export of class II HDACs. OSS induced the association of HDAC‐1/2/3 with Nrf2 and HDAC‐3/5/7 with myocyte enhancer factor‐2, and the deacetylations of these HDACs led to down‐regulations of the antioxidant gene NAD(P)H quinone oxidoreductase‐1 (NQO1) and KLF2 in ECs. Transfecting ECs with HDAC‐1/2/3‐ and HDAC‐3/5/7‐specific small interfering RNAs eliminated the OSS‐induced down‐regulations of NQO1 and KLF2, respectively. OSS up‐regulated cyclin A and phospho‐retinoblastoma and down‐regulated p21 CIP1 in ECs and hence their proliferation; these effects are mediated by HDAC‐1/2/3. The OSS‐induced HDAC signaling and EC responses are mediated by phosphatidylinositol 3‐kinase/Akt. Immunohistochemical examinations of the experimentally stenosed rat abdominal aorta showed high levels of HDAC‐2/3/5 in the EC layer at post‐stenotic sites, where OSS occurs. Our findings indicate the importance of different HDACs in regulating endothelial oxidative, inflammatory, and proliferative responses to disturbed flow with OSS.