Flow-dependent regulation of krüppel-like factor 2 is mediated by MicroRNA-92a

Wei Wu, Han Xiao, Andrés Laguna-Fernandez, Guadalupe Villarreal, Kuei Chun Wang, Greg G. Geary, Yuzhi Zhang, Wei Chi Wang, Hsien Da Huang, Jing Zhou, Yi Shuan Li, Shu Chien, Guillermo Garcia-Cardena, John Y.J. Shyy

Research output: Contribution to journalArticlepeer-review

200 Scopus citations

Abstract

Background-Upregulated by atheroprotective flow, the transcription factor Krüppel-like factor 2 (KLF2) is crucial for maintaining endothelial function. MicroRNAs (miRNAs) are noncoding small RNAs that regulate gene expression at the posttranscriptional level. We examined the role of miRNAs, particularly miR-92a, in the atheroprotective flow-regulated KLF2. Methods and Results-Dicer knockdown increased the level of KLF2 mRNA in human umbilical vein endothelial cells, suggesting that KLF2 is regulated by miRNA. In silico analysis predicted that miR-92a could bind to the 3′ untranslated region of KLF2 mRNA. Overexpression of miR-92a decreased the expression of KLF2 and the KLF2-regulated endothelial nitric oxide synthase and thrombomodulin at mRNA and protein levels. A complementary finding is that miR-92a inhibitor increased the mRNA and protein expression of KLF2, endothelial nitric oxide synthase, and thrombomodulin. Subsequent studies revealed that atheroprotective laminar flow downregulated the level of miR-92a precursor to induce KLF2, and the level of this flow-induced KLF2 was reduced by miR-92a precursor. Furthermore, miR-92a level was lower in human umbilical vein endothelial cells exposed to the atheroprotective pulsatile shear flow than under atheroprone oscillatory shear flow. Anti-Ago1/2 immunoprecipitation coupled with real-time polymerase chain reaction revealed that pulsatile shear flow decreased the functional targeting of miR-92a precursor/KLF2 mRNA in human umbilical vein endothelial cells. Consistent with these findings, mouse carotid arteries receiving miR-92a precursor exhibited impaired vasodilatory response to flow. Conclusions- Atheroprotective flow patterns decrease the level of miR-92a, which in turn increases KLF2 expression to maintain endothelial homeostasis.

Original languageEnglish (US)
Pages (from-to)633-641
Number of pages9
JournalCirculation
Volume124
Issue number5
DOIs
StatePublished - Aug 2 2011

Keywords

  • Endothelial cells
  • KLF2
  • MiRNA
  • Shear stress
  • Vasodilation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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