Cheng Yunhui, Liu Xiaojun, Yang Jian, Lin Ying, Xu Da-Zhong, Lu Qi, Deitch Edwin A, Huo Yuqing, Delphin Ellise S, Zhang Chunxiang
Department of Anesthesiology, New Jersey Medical School, UMDNJ, 185 South Orange Ave, MSB-E548, Newark, NJ 07101, USA.
Circ Res. 2009 Jul 17;105(2):158-66. doi: 10.1161/CIRCRESAHA.109.197517. Epub 2009 Jun 18.
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.
血管平滑肌细胞（VSMCs）的表型调节在多种增殖性血管疾病的发病机制中起着关键作用。最近，我们发现微小RNA（miRNA）miR - 145是正常血管壁和新鲜分离的VSMCs中最丰富的miRNA；然而，miR - 145在VSMC表型调节和血管疾病中的作用目前尚不清楚。在这里，我们发现miR - 145在血管壁的VSMCs中选择性表达，并且在形成新生内膜病变的血管壁和培养的去分化VSMCs中其表达显著下调。更重要的是，无论是在体外培养的大鼠VSMCs中还是在体内球囊损伤的大鼠颈动脉中，我们都证明非编码RNA miR - 145是VSMCs的一种新型表型标志物和新型表型调节剂。VSMC分化标志物基因，如平滑肌α - 肌动蛋白、钙调蛋白和SM - 肌球蛋白重链，在pre - miR - 145或表达miR - 145的腺病毒（Ad - miR - 145）作用下上调，但在miR - 145抑制剂2'- OMe - miR - 145作用下下调。我们进一步确定miR - 145介导的VSMCs表型调节是通过其靶基因KLF5及其下游信号分子心肌素实现的。最后，通过Ad - miR - 145在球囊损伤动脉中恢复miR - 145可抑制新生内膜生长。我们得出结论，miR - 145是一种新型的VSMC表型标志物和调节剂，能够控制血管新生内膜病变的形成。这些新发现可能对多种增殖性血管疾病的诊断和治疗具有广泛的意义。
