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Fluid shear stress stimulates phosphorylation-dependent nuclear export of HDAC5 and mediates expression of KLF2 and eNOS
- Source :
- Blood. 115(14)
- Publication Year :
- 2010
-
Abstract
- Fluid shear stress generated by steady laminar blood flow protects vessels from atherosclerosis. Krüppel-like factor 2 (KLF2) and endothelial nitric oxide synthase (eNOS) are fluid shear stress–responsive genes and key mediators in flow anti-inflammatory and antiatherosclerotic actions. However, the molecular mechanisms underlying flow induction of KLF2 and eNOS remain largely unknown. Here, we show a novel role of histone deacetylase 5 (HDAC5) in flow-mediated KLF2 and eNOS expression. We found for the first time that fluid shear stress stimulated HDAC5 phosphorylation and nuclear export in endothelial cells through a calcium/calmodulin-dependent pathway. Consequently, flow induced the dissociation of HDAC5 and myocyte enhancer factor-2 (MEF2) and enhanced MEF2 transcriptional activity, which leads to expression of KLF2 and eNOS. Adenoviral overexpression of a HDAC5 phosphorylation–defective mutant (Ser259/Ser498 were replaced by Ala259/Ala498, HDAC5-S/A), which shows resistance to flow-induced nuclear export, suppressed flow-mediated MEF2 transcriptional activity and expression of KLF2 and eNOS. Importantly, HDAC5-S/A attenuated the flow-inhibitory effect on monocyte adhesion to endothelial cells. Taken together, our results reveal that phosphorylation-dependent derepression of HDAC5 mediates flow-induced KLF2 and eNOS expression as well as flow anti-inflammation, and suggest that HDAC5 could be a potential therapeutic target for the prevention of atherosclerosis.
- Subjects :
- Mef2
Nitric Oxide Synthase Type III
Immunology
Active Transport, Cell Nucleus
Kruppel-Like Transcription Factors
Mutation, Missense
Biology
Biochemistry
Histone Deacetylases
Monocytes
Adenoviridae
Calmodulin
Vascular Biology
Enos
Stress, Physiological
Cell Adhesion
Humans
Phosphorylation
Nuclear export signal
Regulation of gene expression
Cell Nucleus
Histone deacetylase 5
Endothelial Cells
Cell Biology
Hematology
biology.organism_classification
Atherosclerosis
Molecular biology
Cell biology
Nitric oxide synthase
Amino Acid Substitution
Gene Expression Regulation
KLF2
biology.protein
Calcium
Blood Flow Velocity
Subjects
Details
- ISSN :
- 15280020
- Volume :
- 115
- Issue :
- 14
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....a89dd18271c4d9f962674019176b016d