title: MicroRNA-203 mimics age-related aortic smooth muscle dysfunction of cytoskeletal pathways.
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.
authors: Department of Health Sciences, Boston University, Boston, MA, USA.
authors: Christopher J
authors: CJ
authors: Nicholson
authors: Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
authors: Francesca
authors: F
authors: Seta
authors: Department of Health Sciences, Boston University, Boston, MA, USA.
authors: Sophie
authors: S
authors: Lee
authors: Department of Health Sciences, Boston University, Boston, MA, USA.
authors: Kathleen G
authors: KG
authors: Morgan
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology*; D051242:Caveolin 1 / Q000235:genetics; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology*; D051419:Paxillin / Q000235:genetics; D010656:Phenylephrine / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D059289:Vascular Stiffness / Q000187:drug effects / Q000235:genetics
chemical_list: D051242:Caveolin 1; C575934:MIRN203 microRNA, mouse; D035683:MicroRNAs; D051419:Paxillin; D010656:Phenylephrine
keywords: aortic stiffness; cytoskeleton; focal adhesion; microRNA; vascular smooth muscle