MicroRNA-31 controls phenotypic modulation of human vascular smooth muscle cells by regulating its target gene cellular repressor of E1A-stimulated genes.

Phenotypic modulation of vascular smooth muscle cells (VSMCs) plays a critical role in the pathogenesis of a variety of proliferative vascular diseases. The cellular repressor of E1A-stimulated genes (CREG) has been shown to play an important role in phenotypic modulation of VSMCs. However, the mechanism regulating CREG upstream signaling remains unclear. MicroRNAs (miRNAs) have recently been found to play a critical role in cell differentiation via target-gene regulation. This study aimed to identify a miRNA that binds directly to CREG, and may thus be involved in CREG-mediated VSMC phenotypic modulation. Computational analysis indicated that miR-31 bound to the CREG mRNA 3' untranslated region (3'-UTR). miR-31 was upregulated in quiescent differentiated VSMCs and downregulated in proliferative cells stimulated by platelet-derived growth factor and serum starvation, demonstrating a negative relationship with the VSMC differentiation marker genes, smooth muscle α-actin, calponin and CREG. Using gain-of-function and loss-of-function approaches, CREG and VSMC differentiation marker gene expression levels were shown to be suppressed by a miR-31 mimic, but increased by a miR-31 inhibitor at both protein and mRNA levels. Notably, miR-31 overexpression or inhibition affected luciferase expression driven by the CREG 3'-UTR containing the miR-31 binding site. Furthermore, miR-31-mediated VSMC phenotypic modulation was inhibited in CREG-knockdown human VSMCs. We also determined miR-31 levels in the serum of patients with coronary artery disease (CAD), with or without in stent restenosis and in healthy controls. miR-31 levels were higher in the serum of CAD patients with restenosis compared to CAD patients without restenosis and in healthy controls. In summary, these data demonstrate that miR-31 not only directly binds to its target gene CREG and modulates the VSMC phenotype through this interaction, but also can be an important biomarker in diseases involving VSMC phenotypic modulation. These novel findings may have extensive implications for the diagnosis and therapy of a variety of proliferative vascular diseases.

Wang J ，Yan CH ，Li Y ，Xu K ，Tian XX ，Peng CF ，Tao J ，Sun MY ，Han YL ... -  《-》

[Expression of cellular repressor of E1A-stimulated genes in vascular smooth muscle cells of different phenotypes].

Han YL ，Liu HW ，Kang J ，Yan CH ，Wang XZ ，Zhao LY ，Li SH ... -  《-》

MicroRNA-133 controls vascular smooth muscle cell phenotypic switch in vitro and vascular remodeling in vivo.

Torella D ，Iaconetti C ，Catalucci D ，Ellison GM ，Leone A ，Waring CD ，Bochicchio A ，Vicinanza C ，Aquila I ，Curcio A ，Condorelli G ，Indolfi C ... -  《-》

CREG promotes a mature smooth muscle cell phenotype and reduces neointimal formation in balloon-injured rat carotid artery.

Han Y ，Deng J ，Guo L ，Yan C ，Liang M ，Kang J ，Liu H ，Graham AM ，Li S ... -  《CARDIOVASCULAR RESEARCH》

[Over-expression of the cellular repressor of E1A-stimulated genes inhibits the apoptosis of human vascular smooth muscle cells in vitro.].

Han YL ，Xu HM ，Deng J ，Hu Y ，Kang J ，Liu HW ，Yan CH ... -  《-》