Decorin GAG Synthesis and TGF-beta Signaling Mediate Ox-LDL-Induced Mineralization of Human Vascular Smooth Muscle Cells

作者：Yan Jianyun; Stringer Sally E; Hamilton Andrew; Charlton Menys Valentine; Goetting Christian; Mueller Benjamin; Aeschlimann Daniel; Alexander M Yvonne^*

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2011, 31(3): 608-615.

DOI：10.1161/ATVBAHA.110.220749

• calcification
• glycosominoglycan
• molecular biology
• oxidized lipids
• vascular biology

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.)

• 出版日期2011-3