Published online before print May 3, 2007, doi: 10.1161/CIRCRESAHA.106.141986
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Submitted on October 5, 2006
Revised on March 29, 2007
Accepted on April 23, 2007
MicroRNA Expression Signature and Antisense-Mediated Depletion Reveal an Essential Role of MicroRNA in Vascular Neointimal Lesion Formation
Ruirui Ji ;
From the Cardiovascular Research Laboratory, Vascular Biology Center & Department of Surgery (R.J., Y.C., J. Yang, X.L., H.C., D.B.D., C.Z.), University of Tennessee Health Science Center, Memphis, Tenn; and Magee Women’s Hospital Research Institute (J. Yue), University of Pittsburgh, Pittsburgh, Pa.
* To whom correspondence should be addressed. E-mail: czhang1{at}utmem.edu.
MicroRNAs (miRNAs) are a recently discovered class of endogenous, small, noncoding RNAs that regulate about 30% of the encoding genes of the human genome. However, the role of miRNAs in vascular disease is currently completely unknown. Using microarray analysis, we demonstrated for the first time that miRNAs are aberrantly expressed in the vascular walls after balloon injury. The aberrantly expressed miRNAs were further confirmed by Northern blot and quantitative real-time polymerase chain reaction. Modulating an aberrantly overexpressed miRNA, miR-21, via antisense-mediated depletion (knock-down) had a significant negative effect on neointimal lesion formation. In vitro, the expression level of miR-21 in dedifferentiated vascular smooth muscle cells was significantly higher than that in fresh isolated differentiated cells. Depletion of miR-21 resulted in decreased cell proliferation and increased cell apoptosis in a dose-dependent manner. MiR-21-mediated cellular effects were further confirmed in vivo in balloon-injured rat carotid arteries. Western blot analysis demonstrated that PTEN and Bcl-2 were involved in miR-21-mediated cellular effects. The results suggest that miRNAs are novel regulatory RNAs for neointimal lesion formation. MiRNAs may be a new therapeutic target for proliferative vascular diseases such as atherosclerosis, postangioplasty restenosis, transplantation arteriopathy, and stroke.
Key words: microRNAs • vascular smooth muscle cells • proliferation • apoptosis • neointimal formation
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