A necessary role of miR-221 and miR-222 in vascular smooth muscle cell proliferation and neointimal hyperplasia.
MicroRNAs (miRNAs) comprise a novel class of endogenous, small, noncoding RNAs that negatively regulate gene expression. Functionally, an individual miRNA is as important as a transcription factor because it is able to regulate the expression of its multiple target genes. Recently, miR-221 and miR-222 have been found to play a critical role in cancer cell proliferation. However, their roles in vascular smooth muscle cell (VSMC) biology are currently unknown. In the present study, the time course changes and cellular distribution of miR-221 and miR-222 expression were identified in rat carotid arteries after angioplasty, in which their expression was upregulated and localized in VSMCs in the injured vascular walls. In cultured VSMCs, miR-221 and miR-222 expression was increased by growth stimulators. Knockdown of miR-221 and miR-222 resulted in decreased VSMC proliferation in vitro. Using both gain-of-function and loss-of-function approaches, we found that p27(Kip1) and p57(Kip2) were 2 target genes that were involved in miR-221- and miR-222-mediated effect on VSMC growth. Finally, knockdown of miR-221 and miR-222 in rat carotid arteries suppressed VSMC proliferation in vivo and neointimal lesion formation after angioplasty. The results indicate that miR-221 and miR-222 are novel regulators for VSMC proliferation and neointimal hyperplasia. These findings may also represent promising therapeutic targets in proliferative vascular diseases.
Liu
Xiaojun
X
RNA and Cardiovascular Research Laboratory, Department of Anesthesiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07101, USA.
Cheng
Yunhui
Y
Zhang
Shuo
S
Lin
Ying
Y
Yang
Jian
J
Zhang
Chunxiang
C
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D000077214:Becaplermin; D002340:Carotid Artery Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D017536:Carotid Artery, Common / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000378:metabolism; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D006965:Hyperplasia; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology
C493962:Cdkn1b protein, rat; D050761:Cyclin-Dependent Kinase Inhibitor p57; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D034741:RNA, Small Interfering; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077214:Becaplermin