title: Glycated Collagen Induces α11 Integrin Expression Through TGF-β2 and Smad3.
abstract: 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.
authors: Matrix Dynamics Group, University of Toronto, Toronto, Ontario, Canada.
authors: Ilana
authors: I
authors: Talior-Volodarsky
authors: Matrix Dynamics Group, University of Toronto, Toronto, Ontario, Canada.
authors: Pamma D
authors: PD
authors: Arora
authors: Matrix Dynamics Group, University of Toronto, Toronto, Ontario, Canada.
authors: Yongqiang
authors: Y
authors: Wang
authors: Department of Biomedicine and Centre of Cancer Biomarkers, Norwegian Centre of Excellence, University of Bergen, Bergen, Norway.
authors: Cédric
authors: C
authors: Zeltz
authors: Keenan Research Centre for Biomedical Science of St. Michael Hospital, Toronto, Ontario, Canada.
authors: Kim A
authors: KA
authors: Connelly
authors: Department of Biomedicine and Centre of Cancer Biomarkers, Norwegian Centre of Excellence, University of Bergen, Bergen, Norway.
authors: Donald
authors: D
authors: Gullberg
authors: Matrix Dynamics Group, University of Toronto, Toronto, Ontario, Canada.
authors: Christopher A
authors: CA
authors: McCulloch
mesh_terms: D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism*; D017127:Glycation End Products, Advanced; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D058628:Myofibroblasts / Q000378:metabolism*; D038981:Receptors, Collagen / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism*; D053781:Transforming Growth Factor beta2 / Q000378:metabolism*; D000093844:Glycated Proteins
chemical_list: D003094:Collagen; D005353:Fibronectins; D017127:Glycation End Products, Advanced; D016023:Integrins; D038981:Receptors, Collagen; D051899:Smad2 Protein; D051900:Smad3 Protein; D053781:Transforming Growth Factor beta2; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C045099:glycated fibronectin; D000093844:Glycated Proteins; C467800:integrin alpha11beta1