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

Abstract

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 inmore » 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. - Highlights: ► MiR-31 modulates CREG expression by binding directly to the human CREG mRNA 3′-UTR. ► MiR-31 mediates the human VSMC phenotypic modulation by regulating the expression of human CREG. ► Serum miR-31 may act as an important biomarker in diseases involving in stent restenosis after PCI.« less

Authors:
 [1];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2]
  1. Xijing Hospital, Fourth Military Medical University, Xi'an 710032 (China)
  2. Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Shenyang 110840 (China)
Publication Date:
OSTI Identifier:
22278237
Resource Type:
Journal Article
Journal Name:
Experimental Cell Research
Additional Journal Information:
Journal Volume: 319; Journal Issue: 8; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0014-4827
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACTIN; BIOLOGICAL MARKERS; CELL DIFFERENTIATION; CORONARIES; DIAGNOSIS; GENE REGULATION; GENES; GROWTH FACTORS; LUCIFERASE; MESSENGER-RNA; VASCULAR DISEASES

Citation Formats

Wang, Jie, Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Shenyang 110840, Yan, Cheng-Hui, Li, Yang, Xu, Kai, Tian, Xiao-Xiang, Peng, Cheng-Fei, Tao, Jie, Sun, Ming-Yu, and Han, Ya-Ling. MicroRNA-31 controls phenotypic modulation of human vascular smooth muscle cells by regulating its target gene cellular repressor of E1A-stimulated genes. United States: N. p., 2013. Web. doi:10.1016/J.YEXCR.2013.03.010.
Wang, Jie, Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Shenyang 110840, Yan, Cheng-Hui, Li, Yang, Xu, Kai, Tian, Xiao-Xiang, Peng, Cheng-Fei, Tao, Jie, Sun, Ming-Yu, & Han, Ya-Ling. MicroRNA-31 controls phenotypic modulation of human vascular smooth muscle cells by regulating its target gene cellular repressor of E1A-stimulated genes. United States. https://doi.org/10.1016/J.YEXCR.2013.03.010
Wang, Jie, Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Shenyang 110840, Yan, Cheng-Hui, Li, Yang, Xu, Kai, Tian, Xiao-Xiang, Peng, Cheng-Fei, Tao, Jie, Sun, Ming-Yu, and Han, Ya-Ling. Wed . "MicroRNA-31 controls phenotypic modulation of human vascular smooth muscle cells by regulating its target gene cellular repressor of E1A-stimulated genes". United States. https://doi.org/10.1016/J.YEXCR.2013.03.010.
@article{osti_22278237,
title = {MicroRNA-31 controls phenotypic modulation of human vascular smooth muscle cells by regulating its target gene cellular repressor of E1A-stimulated genes},
author = {Wang, Jie and Cardiovascular Research Institute and Key Laboratory of Cardiology, Shenyang Northern Hospital, Shenyang 110840 and Yan, Cheng-Hui and Li, Yang and Xu, Kai and Tian, Xiao-Xiang and Peng, Cheng-Fei and Tao, Jie and Sun, Ming-Yu and Han, Ya-Ling},
abstractNote = {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. - Highlights: ► MiR-31 modulates CREG expression by binding directly to the human CREG mRNA 3′-UTR. ► MiR-31 mediates the human VSMC phenotypic modulation by regulating the expression of human CREG. ► Serum miR-31 may act as an important biomarker in diseases involving in stent restenosis after PCI.},
doi = {10.1016/J.YEXCR.2013.03.010},
url = {https://www.osti.gov/biblio/22278237}, journal = {Experimental Cell Research},
issn = {0014-4827},
number = 8,
volume = 319,
place = {United States},
year = {2013},
month = {5}
}