Fluid shear stress stimulates phosphorylation-dependent nuclear export of HDAC5 and mediates expression of KLF2 and eNOS.
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.
Wang
Weiye
W
Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Ha
Chang Hoon
CH
Jhun
Bong Sook
BS
Wong
Chelsea
C
Jain
Mukesh K
MK
Jin
Zheng-Gen
ZG
D021581:Active Transport, Cell Nucleus; D000256:Adenoviridae; D019943:Amino Acid Substitution; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D001783:Blood Flow Velocity; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006655:Histone Deacetylases; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis*; D010766:Phosphorylation / Q000235:genetics; D013312:Stress, Physiological
D002147:Calmodulin; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C404500:HDAC5 protein, human; D006655:Histone Deacetylases; D002118:Calcium