367 Alpha 11 Integrin Mediates the Formation of Pro-Fibrotic Cells in Diabetic Cardiomyopathy

Abstract

BackgroundDiabetic 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 extracellular matrix collagens mediates the differentiation of pro-fibrotic myofibroblasts, which may contribute to cardiac fibrosis.Methods/ResultsBy microarray we found that methylglyoxal-treated collagen selectively enhanced α11 integrin expression in human cardiac fibroblasts (HCF) while levels of other collagen binding integrins (α1, α2 and α10) were unchanged. Similar increases of α11 integrin mRNA and protein expression were observed in cardiac fibroblasts (RCF) from streptozotocin-treated Sprague Dawley rats. In HCF plated on methyglyoxal-treated collagen and in RCF from diabetic rats, TGF-β2 but not TGF-β1 or TGF-β3 was increased compared to controls. Knock down of α11 integrin and TGF-β receptors with small interfering RNA blocked the increased expression of TGF-β2, α-SMA and α11 integrin that were induced in cells plated on methylglyoxal-treated collagen. Further, inhibition of Smad3 signaling with SIS3 blocked MGO-collagen up-regulation of α11 integrin and α-SMA expression. Rats with streptozotocin-induced diabetes exhibited increased phosphorylation of Smad 3 in cardiac tissues compared with control rats.ConclusionInteractions between α11 integrins and the Smad-dependent TGF-β2 signaling may contribute to the formation of pro-fibrotic myofibroblasts and the development of a fibrotic interstitium in diabetic cardiomyopathy.HSFC BackgroundDiabetic 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 extracellular matrix collagens mediates the differentiation of pro-fibrotic myofibroblasts, which may contribute to cardiac fibrosis. 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 extracellular matrix collagens mediates the differentiation of pro-fibrotic myofibroblasts, which may contribute to cardiac fibrosis. Methods/ResultsBy microarray we found that methylglyoxal-treated collagen selectively enhanced α11 integrin expression in human cardiac fibroblasts (HCF) while levels of other collagen binding integrins (α1, α2 and α10) were unchanged. Similar increases of α11 integrin mRNA and protein expression were observed in cardiac fibroblasts (RCF) from streptozotocin-treated Sprague Dawley rats. In HCF plated on methyglyoxal-treated collagen and in RCF from diabetic rats, TGF-β2 but not TGF-β1 or TGF-β3 was increased compared to controls. Knock down of α11 integrin and TGF-β receptors with small interfering RNA blocked the increased expression of TGF-β2, α-SMA and α11 integrin that were induced in cells plated on methylglyoxal-treated collagen. Further, inhibition of Smad3 signaling with SIS3 blocked MGO-collagen up-regulation of α11 integrin and α-SMA expression. Rats with streptozotocin-induced diabetes exhibited increased phosphorylation of Smad 3 in cardiac tissues compared with control rats. By microarray we found that methylglyoxal-treated collagen selectively enhanced α11 integrin expression in human cardiac fibroblasts (HCF) while levels of other collagen binding integrins (α1, α2 and α10) were unchanged. Similar increases of α11 integrin mRNA and protein expression were observed in cardiac fibroblasts (RCF) from streptozotocin-treated Sprague Dawley rats. In HCF plated on methyglyoxal-treated collagen and in RCF from diabetic rats, TGF-β2 but not TGF-β1 or TGF-β3 was increased compared to controls. Knock down of α11 integrin and TGF-β receptors with small interfering RNA blocked the increased expression of TGF-β2, α-SMA and α11 integrin that were induced in cells plated on methylglyoxal-treated collagen. Further, inhibition of Smad3 signaling with SIS3 blocked MGO-collagen up-regulation of α11 integrin and α-SMA expression. Rats with streptozotocin-induced diabetes exhibited increased phosphorylation of Smad 3 in cardiac tissues compared with control rats. ConclusionInteractions between α11 integrins and the Smad-dependent TGF-β2 signaling may contribute to the formation of pro-fibrotic myofibroblasts and the development of a fibrotic interstitium in diabetic cardiomyopathy.HSFC Interactions between α11 integrins and the Smad-dependent TGF-β2 signaling may contribute to the formation of pro-fibrotic myofibroblasts and the development of a fibrotic interstitium in diabetic cardiomyopathy.