Abstract
Endothelial to mesenchymal transition (EndoMT) has been proposed to be involved in the loss of microvascular capillaries in the pathophysiology of fibrosis and organ failure. In EndoMT, endothelial cells (EC) undergo a mesenchymal transition associated with the loss of cell-cell contacts and the acquisition of a synthetic, contractile phenotype. Here, we sought to identify microRNAs (miRNAs) that could play a central role in regulating EndoMT. In a TGF-β dependent in vitro model for EndoMT, we identified miRNAs that were differentially expressed in normoxic and hypoxic conditions. These studies identified miR-155 to be significantly upregulated in EndoMT, an effect that was enhanced under hypoxia, which further augments EndoMT. Silencing of miR-155 directly increased RhoA expression and activity in endothelial cells and affected phosphorylation of downstream LIMK. In contrast, overexpression of miR-155 counteracted RhoA function. Using a selective Rho kinase inhibitor, we could partly suppress EndoMT, strengthening the notion that RhoA plays a central role in EndoMT. Forced overexpression of miR-155 completely suppressed EndoMT, as evidenced by the maintenance of EC characteristics and blocking the acquisition of a mesenchymal phenotype, as compared to control cells. Our data demonstrate that miRNA-155 functions as a negative regulator of RhoA signaling in TGF-β-induced endothelial to mesenchymal transition.
Keywords: microRNA, microRNA-155, EndoMT, antagomiR, RhoA, TGFβ, hypoxia, phosphorylation, mesenchymal, cytoskeleton.
MicroRNA
Title:MicroRNA-155 Functions as a Negative Regulator of RhoA Signaling in TGF-β-induced Endothelial to Mesenchymal Transition
Volume: 1 Issue: 1
Author(s): R. Bijkerk, R. G. de Bruin, C. van Solingen, J. M.G.J. Duijs, K. Kobayashi, E. P. van der Veer, P. ten Dijke, T. J. Rabelink, M. J. Goumans and A. J. van Zonneveld
Affiliation:
Keywords: microRNA, microRNA-155, EndoMT, antagomiR, RhoA, TGFβ, hypoxia, phosphorylation, mesenchymal, cytoskeleton.
Abstract: Endothelial to mesenchymal transition (EndoMT) has been proposed to be involved in the loss of microvascular capillaries in the pathophysiology of fibrosis and organ failure. In EndoMT, endothelial cells (EC) undergo a mesenchymal transition associated with the loss of cell-cell contacts and the acquisition of a synthetic, contractile phenotype. Here, we sought to identify microRNAs (miRNAs) that could play a central role in regulating EndoMT. In a TGF-β dependent in vitro model for EndoMT, we identified miRNAs that were differentially expressed in normoxic and hypoxic conditions. These studies identified miR-155 to be significantly upregulated in EndoMT, an effect that was enhanced under hypoxia, which further augments EndoMT. Silencing of miR-155 directly increased RhoA expression and activity in endothelial cells and affected phosphorylation of downstream LIMK. In contrast, overexpression of miR-155 counteracted RhoA function. Using a selective Rho kinase inhibitor, we could partly suppress EndoMT, strengthening the notion that RhoA plays a central role in EndoMT. Forced overexpression of miR-155 completely suppressed EndoMT, as evidenced by the maintenance of EC characteristics and blocking the acquisition of a mesenchymal phenotype, as compared to control cells. Our data demonstrate that miRNA-155 functions as a negative regulator of RhoA signaling in TGF-β-induced endothelial to mesenchymal transition.
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Bijkerk R., G. de Bruin R., van Solingen C., M.G.J. Duijs J., Kobayashi K., P. van der Veer E., ten Dijke P., J. Rabelink T., J. Goumans M. and J. van Zonneveld A., MicroRNA-155 Functions as a Negative Regulator of RhoA Signaling in TGF-β-induced Endothelial to Mesenchymal Transition, MicroRNA 2012; 1 (1) . https://dx.doi.org/10.2174/2211536611201010002
DOI https://dx.doi.org/10.2174/2211536611201010002 |
Print ISSN 2211-5366 |
Publisher Name Bentham Science Publisher |
Online ISSN 2211-5374 |
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