標題: Flow-Dependent Regulation of Kruppel-Like Factor 2 Is Mediated by MicroRNA-92a
作者: Wu, Wei
Xiao, Han
Laguna-Fernandez, Andres
Villarreal, Guadalupe, Jr.
Wang, Kuei-Chun
Geary, Greg G.
Zhang, Yuzhi
Wang, Wei-Chi
Huang, Hsien-Da
Zhou, Jing
Li, Yi-Shuan
Chien, Shu
Garcia-Cardena, Guillermo
Shyy, John Y-J
生物資訊及系統生物研究所
Institude of Bioinformatics and Systems Biology
關鍵字: endothelial cells;KLF2;miRNA;shear stress;vasodilation
公開日期: 2-Aug-2011
摘要: Background-Upregulated by atheroprotective flow, the transcription factor Kruppel-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. (Circulation. 2011;124:633-641.)
URI: http://dx.doi.org/10.1161/CIRCULATIONAHA.110.005108
http://hdl.handle.net/11536/20507
ISSN: 0009-7322
DOI: 10.1161/CIRCULATIONAHA.110.005108
期刊: CIRCULATION
Volume: 124
Issue: 5
起始頁: 633
結束頁: U231
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