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Decorin GAG synthesis and TGF-beta signaling mediate Ox-LDL-induced mineralization of human vascular smooth muscle cells

Yan, Jianyun Yan, Stringer, Sally E., Hamilton, Andrew, Charlton-Menys, Valentine, Götting, Christian, Müller, B., Aeschlimann, Daniel and Alexander, M. Yvonne 2011. Decorin GAG synthesis and TGF-beta signaling mediate Ox-LDL-induced mineralization of human vascular smooth muscle cells. Arteriosclerosis Thrombosis and Vascular Biology 31 (3) , pp. 608-615. 10.1161/atvbaha.110.220749

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Abstract

Objective-Decorin and oxidized low-density lipoprotein (Ox-LDL) independently induce osteogenic differentiation of vascular smooth muscle cells (VSMCs). We aimed to determine whether decorin glycosaminoglycan (GAG) chain synthesis contributes to Ox-LDL-induced differentiation and calcification of human VSMCs in vitro. Methods and Results-Human VSMCs treated with Ox-LDL to induce oxidative stress showed increased alkaline phosphatase (ALP) activity, accelerated mineralization, and a difference in both decorin GAG chain biosynthesis and CS/DS structure compared with untreated controls. Ox-LDL increased mRNA abundance of both xylosyltransferase (XT)-I, the key enzyme responsible for GAG chain biosynthesis and Msx2, a marker of osteogenic differentiation. Furthermore, downregulation of XT-I expression using small interfering RNA blocked Ox-LDL-induced VSMC mineralization. Adenoviral-mediated overexpression of decorin, but not a mutated unglycanated form, accelerated mineralization of VSMCs, suggesting GAG chain addition on decorin is crucial for the process of differentiation. The decorin-induced VSMC osteogenic differentiation involved activation of the transforming growth factor (TGF)-beta pathway, because it was attenuated by blocking of TGF-beta receptor signaling and because decorin overexpression potentiated phosphorylation of the downstream signaling molecule smad2. Conclusion-These studies provide direct evidence that oxidative stress-mediated decorin GAG chain synthesis triggers TGF-beta signaling and mineralization of VSMCs in vitro.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Dentistry
Subjects: Q Science > QH Natural history > QH301 Biology
Uncontrolled Keywords: calcification ; glycosominoglycan ; molecular biology ; oxidized lipids ; vascular biology
Additional Information: Pdf uploaded in accordance with publisher's policy at http://www.sherpa.ac.uk/romeo/issn/1079-5642/ (accessed 19/02/2014).
Publisher: American Heart Association, Inc.
ISSN: 1079-5642
Date of First Compliant Deposit: 30 March 2016
Last Modified: 04 Jun 2017 03:04
URI: http://orca.cf.ac.uk/id/eprint/16127

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