Journal
CARDIOVASCULAR RESEARCH
Volume 90, Issue 3, Pages 464-474Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvr017
Keywords
Vascular smooth muscle; SM22 alpha; Kruppel-like factor 4; All-trans retinoic acid; Platelet-derived growth factor-BB
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Funding
- National Natural Science Foundation of China [30971457, 90919035, 30871272, 31071003]
- Natural Science Foundation of Hebei Province [C2008001049, C2009001541]
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Aims Kruppel-like factor 4 (KLF4) is implicated in all-trans retinoic acid (ATRA)-induced and platelet-derived growth factor-BB (PDGF-BB)-repressed SM22 alpha expression in vascular smooth muscle cells (VSMCs). However, its exact mechanism of action remains unclear. We determined how KLF4 plays different roles in ATRA- and PDGF-BB-dependent regulation of the SM22 alpha gene. Methods and results ATRA and PDGF-BB induced KLF4 expression but exhibited an opposite effect on SM22 alpha expression and VSMC proliferation. Chromatin immunoprecipitation and oligonucleotide pull-down assays showed that KLF4 was directly bound to the KLF4 binding sites 1 ((-263)CACCC(-259)) and 2 ((-136)GTGGG(-132)) of the SM22 alpha promoter. ATRA increased the binding of KLF4 to site 2, whereas PDGF-BB decreased the binding of KLF4 to site 1. ATRA stimulated KLF4 acetylation by inducing KLF4 phosphorylation and increasing its interaction with p300 via activating c-Jun NH(2)-terminal kinase (JNK) and p38 pathways, and acetylated KLF4 increased its binding activity to site 2. PDGF-BB stimulated KLF4 deacetylation by inducing KLF4 dephosphorylation and increasing its interaction with histone deacetylase 2 (HDAC2) via activating extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathways, and deacetylated KLF4 dissociated from site 1. Conclusions In VSMCs, ATRA activates and PDGF-BB represses SM22 alpha expression through KLF4 binding to, or dissociating from, its different cis-elements in an acetylation-dependent manner.
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