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Histone deacetylase 5 interacts with Krüppel-like factor 2 and inhibits its transcriptional activity in endothelium
- Source :
- Cardiovascular research. 104(1)
- Publication Year :
- 2014
-
Abstract
- Aims Vascular endothelial dysfunction and inflammation are hallmarks of atherosclerosis. Kruppel-like factor 2 (KLF2) is a key mediator of anti-inflammatory and anti-atherosclerotic properties of the endothelium. However, little is known of the molecular mechanisms for regulating KLF2 transcriptional activation. Methods and results Here, we found that histone deacetylase 5 (HDAC5) associates with KLF2 and represses KLF2 transcriptional activation. HDAC5 resided with KLF2 in the nuclei of human umbilical cord vein endothelial cells (HUVECs). Steady laminar flow attenuated the association of HDAC5 with KLF2 via stimulating HDAC5 phosphorylation-dependent nuclear export in HUVEC. We also mapped the KLF2–HDAC5-interacting domains and found that the N-terminal region of HDAC5 interacts with the C-terminal domain of KLF2. Chromatin immunoprecipitation and luciferase reporter assays showed that HDAC5 through a direct association with KLF2 suppressed KLF2 transcriptional activation. HDAC5 overexpression inhibited KLF2-dependent endothelial nitric oxide synthesis (eNOS) promoter activity in COS7 cell and gene expression in both HUVECs and bovine aortic endothelial cells (BAECs). Conversely, HDAC5 silencing enhanced KLF2 transcription and hence eNOS expression in HUVEC. Moreover, we observed that the level of eNOS protein in the thoracic aorta isolated from HDAC5 knockout mice was higher, whereas expression of pro-inflammatory vascular cell adhesion molecule 1 was lower, compared with those of HDAC5 wild-type mice. Conclusions We reveal a novel role of HDAC5 in modulating the KLF2 transcriptional activation and eNOS expression. These findings suggest that HDAC5, a binding partner and modulator of KLF2, could be a new therapeutic target to prevent vascular endothelial dysfunction associated with cardiovascular diseases.
- Subjects :
- Transcriptional Activation
Endothelium
Nitric Oxide Synthase Type III
Transcription, Genetic
Physiology
Active Transport, Cell Nucleus
Kruppel-Like Transcription Factors
Transfection
Gene Expression Regulation, Enzymologic
Histone Deacetylases
Mediator
Enos
Physiology (medical)
Chlorocebus aethiops
medicine
Human Umbilical Vein Endothelial Cells
Animals
Humans
Protein Interaction Domains and Motifs
Endothelial dysfunction
Phosphorylation
Promoter Regions, Genetic
Mice, Knockout
Histone deacetylase 5
biology
Original Articles
medicine.disease
biology.organism_classification
Molecular biology
Mice, Inbred C57BL
medicine.anatomical_structure
KLF2
COS Cells
Cattle
Histone deacetylase
Stress, Mechanical
Cardiology and Cardiovascular Medicine
Chromatin immunoprecipitation
Protein Binding
Subjects
Details
- ISSN :
- 17553245
- Volume :
- 104
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Cardiovascular research
- Accession number :
- edsair.doi.dedup.....73936bdfe41f969b2c3a44cdaa9384e0