title: α11 integrin stimulates myofibroblast differentiation in diabetic cardiomyopathy.
abstract: OBJECTIVE
  Diabetic cardiomyopathy is characterized by the production of a disorganized fibrotic matrix in the absence of coronary atherosclerosis and hypertension. We examined whether adhesion of cardiac fibroblasts to glycated collagens mediates the differentiation of pro-fibrotic myofibroblasts, which may contribute to cardiac fibrosis.
  
  
  RESULTS
  By microarray, we found that methylglyoxal-treated collagen selectively enhanced α11 integrin expression in human cardiac fibroblasts, while levels of other collagen-binding integrins (α1, α2, and α10) were unchanged. Similar increases in α11 integrin mRNA and protein expression were observed in cardiac fibroblasts from streptozotocin (STZ)-treated Sprague-Dawley rats. In human cardiac fibroblasts plated on methyglyoxal-treated collagen and in cardiac fibroblasts from diabetic rats, transforming growth factor (TGF)-β2 but not TGF-β1 or TGF-β3 was increased compared with controls. Knock-down of α11 integrin and TGF-β receptors with small-interfering RNA blocked the increased expression of TGF-β2, α-smooth muscle actin (α-SMA), and α11 integrin that were induced in cells plated on methylglyoxal-treated collagen. Further, inhibition of Smad3 signalling blocked methylglyoxal-collagen up-regulation of α11 integrin and α-SMA expression. Rats with STZ-induced diabetes exhibited increased phosphorylation of Smad3 in cardiac tissues compared with control rats.
  
  
  CONCLUSIONS
  Interactions between α11 integrins and the Smad-dependent TGF-β2 signalling may contribute to the formation of pro-fibrotic myofibroblasts and the development of a fibrotic interstitium in diabetic cardiomyopathy.
authors.affiliation: Matrix Dynamics Group,  University of Toronto, Room 244, Fitzgerald Building, 150 College Street, Toronto, Ontario,  Canada M5S 3E2.
authors.forename: Ilana
authors.initials: I
authors.lastname: Talior-Volodarsky
authors.forename: Kim A
authors.initials: KA
authors.lastname: Connelly
authors.forename: Pamma D
authors.initials: PD
authors.lastname: Arora
authors.forename: Donald
authors.initials: D
authors.lastname: Gullberg
authors.forename: Christopher A
authors.initials: CA
authors.lastname: McCulloch
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion; D002454:Cell Differentiation; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D039001:Integrin alpha Chains / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000473:pathology*; D058628:Myofibroblasts / Q000473:pathology*; D011765:Pyruvaldehyde; D051381:Rats; D017207:Rats, Sprague-Dawley; D051785:Smad Proteins / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000378:metabolism
chemical_list: D000199:Actins; D003094:Collagen; D039001:Integrin alpha Chains; D011765:Pyruvaldehyde; D051785:Smad Proteins; D053781:Transforming Growth Factor beta2; C541116:ACTA2 protein, human; C121535:ITGA11 protein, human; C558437:ITGA11 protein, rat; C509041:TGFB2 protein, human; C509043:Tgfb2 protein, rat; C498862:Acta2 protein, rat