title: MicroRNA-145, a novel smooth muscle cell phenotypic marker and modulator, controls vascular neointimal lesion formation.
abstract: Phenotypic modulation of vascular smooth muscle cells (VSMCs) plays a critical role in the pathogenesis of a variety of proliferative vascular diseases. Recently, we have found that microRNA (miRNA) miR-145 is the most abundant miRNA in normal vascular walls and in freshly isolated VSMCs; however, the role of miR-145 in VSMC phenotypic modulation and vascular diseases is currently unknown. Here we find that miR-145 is selectively expressed in VSMCs of the vascular wall and its expression is significantly downregulated in the vascular walls with neointimal lesion formation and in cultured dedifferentiated VSMCs. More importantly, both in cultured rat VSMCs in vitro and in balloon-injured rat carotid arteries in vivo, we demonstrate that the noncoding RNA miR-145 is a novel phenotypic marker and a novel phenotypic modulator of VSMCs. VSMC differentiation marker genes such as SM alpha-actin, calponin, and SM-MHC are upregulated by premiR-145 or adenovirus expressing miR-145 (Ad-miR-145) but are downregulated by the miR-145 inhibitor 2'OMe-miR-145. We have further identified that miR-145-mediated phenotypic modulation of VSMCs is through its target gene KLF5 and its downstream signaling molecule, myocardin. Finally, restoration of miR-145 in balloon-injured arteries via Ad-miR-145 inhibits neointimal growth. We conclude that miR-145 is a novel VSMC phenotypic marker and modulator that is able of controlling vascular neointimal lesion formation. These novel findings may have extensive implications for the diagnosis and therapy of a variety of proliferative vascular diseases.
authors: Department of Anesthesiology, New Jersey Medical School, UMDNJ, 185 South Orange Ave, MSB-E548, Newark, NJ 07101, USA.
authors: Yunhui
authors: Y
authors: Cheng
authors: Xiaojun
authors: X
authors: Liu
authors: Jian
authors: J
authors: Yang
authors: Ying
authors: Y
authors: Lin
authors: Da-Zhong
authors: DZ
authors: Xu
authors: Qi
authors: Q
authors: Lu
authors: Edwin A
authors: EA
authors: Deitch
authors: Yuqing
authors: Y
authors: Huo
authors: Ellise S
authors: ES
authors: Delphin
authors: Chunxiang
authors: C
authors: Zhang
mesh_terms: D000818:Animals; D020212:Carotid Artery Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002404:Catheterization / Q000009:adverse effects; D054337:Cell Dedifferentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism; D005786:Gene Expression Regulation; D006965:Hyperplasia; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology; D000099251:Myocardin
chemical_list: D051741:Kruppel-Like Transcription Factors; D035683:MicroRNAs; D009687:Nuclear Proteins; D010982:Platelet-Derived Growth Factor; D015534:Trans-Activators; D000099251:Myocardin; C492215:Klf5 protein, rat; C542511:MIRN145 microRNA, rat