MicroRNA-145, a novel smooth muscle cell phenotypic marker and modulator, controls vascular neointimal lesion formation.
MicroRNA-145, a novel smooth muscle cell phenotypic marker and modulator, controls vascular neointimal lesion formation.
复制标题
DOI：
10.1161/circresaha.109.197517
复制
发表时间：
2009-07-17
影响因子：
20.1
通讯作者：
Zhang C
中科院分区：
文献类型：
--
作者：
Cheng Y;Liu X;Yang J;Lin Y;Xu DZ;Lu Q;Deitch EA;Huo Y;Delphin ES;Zhang C
血管平滑肌细胞(VSMCs)的表型改变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microRNA-145(miR-145)是正常血管壁和新鲜分离的VSMC中含量最丰富的miRNA，但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选择性地表达于血管壁的VSMCs，并且在有新的内膜病变形成的血管壁和培养的去分化的VSMCs中其表达显著下调。更重要的是，在体外培养的大鼠VSMCs和球囊损伤的大鼠颈动脉中，我们证明了非编码RNA miR-145是一种新的VSMCs表型标志物和新的表型调节剂。Smα-Actin、Calponin和SM-MHC等分化标志基因在前MIR145或表达MIR145的腺病毒(Ad-MIR145)中上调，但在MIR145抑制剂2‘OMMIR145的作用下表达下调。我们进一步证实miR-145介导的VSMC表型调控是通过其靶基因KLF5及其下游信号分子myocardin实现的。最后，通过Ad-miR-145修复球囊损伤动脉中的miR-145可抑制新生内膜生长。我们认为miR-145是一种新的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。这些新发现可能对各种增生性血管疾病的诊断和治疗具有广泛的意义。
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-145 (miR-145) is the most abundant miRNA in normal vascular walls and in fresh 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 α-actin, calponin, and SM-MHC are upregulated by pre-miR-145 or adenovirus expressing miR-145 (Ad-miR-145), but are downregulated by 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.