MicroRNA-145, a novel smooth muscle cell phenotypic marker and modulator, controls vascular neointimal lesion formation

By Yun-hui Cheng, Xiaojun Liu, Jian Yang, Ying Lin, Dazhong Xu, Q. Lu, E. Deitch, Yuqing Huo, E. Delphin, Chunxiang Zhang. Circulation Research, 2009

691 citations recorded by the source corpus.

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 α-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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/18b6e851369e85f0c0824943c7eae77bf70450f0

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Citations in the corpus

MicroRNAs miR-143 and miR-145 modulate cytoskeletal dynamics and responsiveness of smooth muscle cells to injury. (2009, background): “Northern blot analysis of adult mouse tissues showed these miRNAs to be especially abundant in the aorta and bladder, rich sources of SMCs (Supplemental Fig. 1A), consistent with recent studies ( Cheng et al. 2009; Cordes et al. 2009).”
MicroRNAs in stress signaling and human disease (2012, background): “Expression of themiR-23a/27a/24-2 cluster is also induced by VEGF-MAPK signaling, establishing another positive feedback loop involving these miRNAs (Cheng et al., 2009; Zhou et al., 2011).”
Mammalian Krüppel-Like Factors in Health and Diseases (2010, background): “MicroRNA (miR)-145, a noncoding RNA that regulates expression of KLFs 4 and 5, is highly expressed in normal vascular walls and freshly isolated vascular SMCs (76, 93).”
Pervasive roles of microRNAs in cardiovascular biology (2011, background): “, and restoration of miR-21 and miR-145 to normal levels prevents restenosi”
MicroRNAs in development and disease. (2011, background): “Given the role of miR145 in VSMC that is described above, it is not surprising to learn that this miRNA is downregulated in response to vascular injury (103).”