Flow-Dependent Regulation of Kruppel-Like Factor 2 Is Mediated by MicroRNA-92a.

  • Wu W
  • Xiao H
  • Laguna-Fernandez A
 et al. 
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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.

Author-supplied keywords

  • 3' Untranslated Regions
  • 3' Untranslated Regions: genetics
  • Atherosclerosis
  • Atherosclerosis: genetics
  • Atherosclerosis: pathology
  • Atherosclerosis: physiopathology
  • Cells, Cultured
  • Endothelial Cells
  • Endothelial Cells: cytology
  • Endothelial Cells: physiology
  • Gene Expression Regulation
  • Gene Expression Regulation: physiology
  • Gene Knockdown Techniques
  • Homeostasis
  • Homeostasis: physiology
  • Humans
  • Kruppel-Like Transcription Factors
  • Kruppel-Like Transcription Factors: genetics
  • Kruppel-Like Transcription Factors: metabolism
  • MicroRNAs
  • MicroRNAs: physiology
  • Nitric Oxide
  • Nitric Oxide Synthase Type III
  • Nitric Oxide Synthase Type III: genetics
  • Nitric Oxide Synthase Type III: metabolism
  • Nitric Oxide: metabolism
  • Pulsatile Flow
  • Pulsatile Flow: physiology
  • RNA, Messenger
  • RNA, Messenger: genetics
  • Stress, Mechanical
  • Thrombomodulin
  • Thrombomodulin: genetics
  • Thrombomodulin: metabolism
  • Umbilical Veins
  • Umbilical Veins: cytology
  • Vasodilation
  • Vasodilation: physiology

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Authors

  • Wei Wu

  • Han Xiao

  • Andrés Laguna-Fernandez

  • Guadalupe Villarreal

  • Kuei-Chun Wang

  • Greg G Geary

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