α11 integrin stimulates myofibroblast differentiation in diabetic cardiomyopathy

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. By microarray, we found that methylglyoxal-treated collagen selectively enhanced 11 integrin expression in human cardiac fibroblasts, while levels of other collagen-binding integrins (1, 2, and 10) were unchanged. Similar increases in 11 integrin mRNA and protein expression were observed in cardiac fibroblasts from streptozotocin (STZ)-treated SpragueDawley rats. In human cardiac fibroblasts plated on methyglyoxal-treated collagen and in cardiac fibroblasts from diabetic rats, transforming growth factor (TGF)-2 but not TGF-1 or TGF-3 was increased compared with controls. Knock-down of 11 integrin and TGF- receptors with small-interfering RNA blocked the increased expression of TGF-2, -smooth muscle actin (-SMA), and 11 integrin that were induced in cells plated on methylglyoxal-treated collagen. Further, inhibition of Smad3 signalling blocked methylglyoxal-collagen up-regulation of 11 integrin and -SMA expression. Rats with STZ-induced diabetes exhibited increased phosphorylation of Smad3 in cardiac tissues compared with control rats. Interactions between 11 integrins and the Smad-dependent TGF-2 signalling may contribute to the formation of pro-fibrotic myofibroblasts and the development of a fibrotic interstitium in diabetic cardiomyopathy.