MicroRNA-23b regulates cyclin-dependent kinase-activating kinase complex through cyclin H repression to modulate endothelial transcription and growth under flow

Kuei Chun Wang, Phu Nguyen, Anna Weiss, Yi Ting Yeh, Hou Su Chien, Alicia Lee, Dayu Teng, Shankar Subramaniam, Yi Shuan Li, Shu Chien

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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. APPROACH AND 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.

Original languageEnglish (US)
Pages (from-to)1437-1445
Number of pages9
JournalArteriosclerosis, thrombosis, and vascular biology
Volume34
Issue number7
DOIs
StatePublished - Jul 2014
Externally publishedYes

Keywords

  • cell cycle
  • endothelial cells
  • hemodynamics
  • microRNAs

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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