MicroRNA-203 mimics age-related aortic smooth muscle dysfunction of cytoskeletal pathways
Date
2017-01-01
Authors
Nicholson, Christopher J.
Seta, Francesca
Lee, Sophie
Morgan, Kathleen G.
Version
Published version
OA Version
Citation
C.J. Nicholson, F. Seta, S. Lee, K.G. Morgan. 2017. "MicroRNA-203 mimics age-related aortic smooth muscle dysfunction of cytoskeletal pathways" Journal of Cellular and Molecular Medicine, Volume 21, Issue 1, pp.81-95. https://doi.org/10.1111/jcmm.12940
Abstract
Increased aortic stiffness is a biomarker for subsequent adverse cardiovascular events. We have previously reported that vascular smooth muscle Src-dependent cytoskeletal remodelling, which contributes to aortic plasticity, is impaired with ageing. Here, we use a multi-scale approach to determine the molecular mechanisms behind defective Src-dependent signalling in an aged C57BL/6 male mouse model. Increased aortic stiffness, as measured in vivo by pulse wave velocity, was found to have a comparable time course to that in humans. Bioinformatic analyses predicted several miRs to regulate Src-dependent cytoskeletal remodelling. qRT-PCR was used to determine the relative levels of predicted miRs in aortas and, notably, the expression of miR-203 increased almost twofold in aged aorta. Increased miR-203 expression was associated with a decrease in both mRNA and protein expression of Src, caveolin-1 and paxillin in aged aorta. Probing with phospho-specific antibodies confirmed that overexpression of miR-203 significantly attenuated Src and extracellular signal regulated kinase (ERK) signalling, which we have previously found to regulate vascular smooth muscle stiffness. In addition, transfection of miR-203 into aortic tissue from young mice increased phenylephrine-induced aortic stiffness ex vivo, mimicking the aged phenotype. Upstream of miR-203, we found that DNA methyltransferases (DNMT) 1, 3a, and 3b are also significantly decreased in the aged mouse aorta and that DNMT inhibition significantly increases miR-203 expression. Thus, the age-induced increase in miR-203 may be caused by epigenetic promoter hypomethylation in the aorta. These findings indicate that miR-203 promotes a re-programming of Src/ERK signalling pathways in vascular smooth muscle, impairing the regulation of stiffness in aged aorta.
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License
© 2016 The Authors. This article is distributed under the terms of the Creative Commons Attribution 4.0 International.