title: MicroRNA-23b regulates cyclin-dependent kinase-activating kinase complex through cyclin H repression to modulate endothelial transcription and growth under flow.
abstract: OBJECTIVE
  The site-specificity of endothelial phenotype is attributable to the local hemodynamic forces. The flow regulation of microRNAs in endothelial cells (ECs) plays a significant role in vascular homeostasis and diseases. The objective of this study was to elucidate the molecular mechanism by which the pulsatile shear flow-induced microRNA-23b (miR-23b) exerts antiproliferative effects on ECs.
  
  
  RESULTS
  We used a combination of a cell perfusion system and experimental animals to examine the flow regulation of miR-23b in modulating EC proliferation. Our results demonstrated that pulsatile shear flow induces the transcription factor Krüppel-like factor 2 to promote miR-23b biosynthesis; the increase in miR-23b then represses cyclin H to impair the activity and integrity of cyclin-dependent kinase-activating kinase (CAK) complex. The inhibitory effect of miR-23b on CAK exerts dual actions to suppress cell cycle progression, and reduce basal transcription by deactivating RNA polymerase II. Whereas pulsatile shear flow regulates the miR-23b/CAK pathway to exert antiproliferative effects on ECs, oscillatory shear flow has little effect on the miR-23b/CAK pathway and hence does not cause EC growth arrest. Such flow pattern-dependent phenomena are validated with an in vivo model on rat carotid artery: the flow disturbance induced by partial carotid ligation led to a lower expression of miR-23b and a higher EC proliferation in comparison with the pulsatile flow regions of the unligated vessels. Local delivery of miR-23b mitigated the proliferative EC phenotype in partially ligated vessels.
  
  
  CONCLUSIONS
  Our findings unveil a novel mechanism by which hemodynamic forces modulate EC proliferative phenotype through the miR-23b/CAK pathway.
authors.affiliation: From the Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla.
authors.forename: Kuei-Chun
authors.initials: KC
authors.lastname: Wang
authors.affiliation: From the Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla.
authors.forename: Phu
authors.initials: P
authors.lastname: Nguyen
authors.affiliation: From the Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla.
authors.forename: Anna
authors.initials: A
authors.lastname: Weiss
authors.affiliation: From the Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Yeh
authors.affiliation: From the Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla.
authors.forename: Hou Su
authors.initials: HS
authors.lastname: Chien
authors.affiliation: From the Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla.
authors.forename: Alicia
authors.initials: A
authors.lastname: Lee
authors.affiliation: From the Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla.
authors.forename: Dayu
authors.initials: D
authors.lastname: Teng
authors.affiliation: From the Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla.
authors.forename: Shankar
authors.initials: S
authors.lastname: Subramaniam
authors.affiliation: From the Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla.
authors.forename: Yi-Shuan
authors.initials: YS
authors.lastname: Li
authors.affiliation: From the Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla. shuchien@ucsd.edu yili@ucsd.edu.
authors.forename: Shu
authors.initials: S
authors.lastname: Chien
mesh_terms: D000818:Animals; D002340:Carotid Artery Diseases / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D002478:Cells, Cultured; D056748:Cyclin H / Q000235:genetics / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology*; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008297:Male; D040542:Mechanotransduction, Cellular; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010477:Perfusion; D010641:Phenotype; D011673:Pulsatile Flow; D034622:RNA Interference; D012319:RNA Polymerase II / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow; D013314:Stress, Mechanical; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: D056748:Cyclin H; D018844:Cyclin-Dependent Kinases; D051741:Kruppel-Like Transcription Factors; D035683:MicroRNAs; D012319:RNA Polymerase II; D000095043:Cyclin-Dependent Kinase-Activating Kinase; C534751:CCNH protein, human; C534753:Ccnh protein, rat; C096161:KLF2 protein, human; C543921:Klf2 protein, rat; C000590974:MIRN23a microRNA, rat; C552430:MIRN23a microRNA, human
keywords: cell cycle; endothelial cells; hemodynamics; microRNAs