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Fluid shear stress stimulates phosphorylation-dependent nuclear export of HDAC5 and mediates expression of KLF2 and eNOS.
- Source :
-
Blood [Blood] 2010 Apr 08; Vol. 115 (14), pp. 2971-9. Date of Electronic Publication: 2009 Dec 30. - 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 :
- Active Transport, Cell Nucleus
Adenoviridae
Amino Acid Substitution
Atherosclerosis genetics
Atherosclerosis metabolism
Atherosclerosis pathology
Atherosclerosis prevention & control
Blood Flow Velocity
Calcium metabolism
Calmodulin genetics
Calmodulin metabolism
Cell Adhesion
Cell Nucleus genetics
Cell Nucleus pathology
Endothelial Cells pathology
Histone Deacetylases
Humans
Kruppel-Like Transcription Factors genetics
Monocytes pathology
Mutation, Missense
Phosphorylation genetics
Cell Nucleus metabolism
Endothelial Cells metabolism
Gene Expression Regulation
Kruppel-Like Transcription Factors biosynthesis
Monocytes metabolism
Nitric Oxide Synthase Type III biosynthesis
Stress, Physiological
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 115
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 20042720
- Full Text :
- https://doi.org/10.1182/blood-2009-05-224824