Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 31, Issue 3, Pages 608-615Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.110.220749
Keywords
calcification; glycosominoglycan; molecular biology; oxidized lipids; vascular biology
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Funding
- Universities UK
- University of Manchester Overseas
- Arthritis Research UK [18461]
- National Institute for Health Research Manchester Biomedical Research Centre
- Manchester Academic Health Science Centre
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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. (Arterioscler Thromb Vasc Biol. 2011;31:608-615.)
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