Glycated Collagen Induces α11 Integrin Expression Through TGF-β2 and Smad3.

Published on Feb 1, 2015in Journal of Cellular Physiology5.546
· DOI :10.1002/JCP.24708
Ilana Talior-Volodarsky8
Estimated H-index: 8
(U of T: University of Toronto),
Pamma D. Arora15
Estimated H-index: 15
(U of T: University of Toronto)
+ 4 AuthorsChristopher A. McCulloch86
Estimated H-index: 86
(U of T: University of Toronto)
The adhesion of cardiac fibroblasts to the glycated collagen interstitium in diabetics is associated with de novo expression of the α11 integrin, myofibroblast formation and cardiac fibrosis. We examined how methylglyoxal-glycated collagen regulates α11 integrin expression. In cardiac fibroblasts plated on glycated collagen but not glycated fibronectin, there was markedly increased α11 integrin and α-smooth muscle actin expression. Compared with native collagen, binding of purified α11β1 integrin to glycated collagen was reduced by >fourfold, which was consistent with reduced fibroblast attachment to glycated collagen. Glycated collagen strongly enhanced the expression of TGF-β2 but not TGF-β1 or TGF-β3. The increased expression of TGF-β2 was inhibited by triple helical collagen peptides that mimic the α11β1 integrin binding site on type I collagen. In cardiac fibroblasts transfected with α11 integrin luciferase promoter constructs, glycated collagen activated the α11 integrin promoter. Analysis of α11 integrin promoter truncation mutants showed a novel Smad2/3 binding site located between −809 and −1300 nt that was required for promoter activation. We conclude that glycated collagen in the cardiac interstitium triggers an autocrine TGF-β2 signaling pathway that stimulates α11 integrin expression through Smad2/3 binding elements in the α11 integrin promoter, which is important for myofibroblast formation and fibrosis. J. Cell. Physiol. 230: 327–336, 2015. © 2014 Wiley Periodicals, Inc.
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