Increased Expression Of Thioredoxin Interacting Protein Promotes Oxidative Stress And Contributes To The Pathogenesis Of Diabetic Cardiomyopathy

Background: Alterations in the thioredoxin (TRX) antioxidant system have been implicated in the pathogenesis of cardiac injury, particularly in the diabetic setting. While constitutively present, TRX activity is reduced by the presence of its endogenous inhibitor, thioredoxin interacting protein (TxnIP). We hypothesized that by increasing TxnIP, diabetes may reduce TRX activity and contribute to oxidative stress. Methods: Cell culture studies were performed using the H9C2 rat cardiomyoblast cell line and neonatal cardiomyocytes isolated from 1 day old Sprague Dawley rat neonates. In-vivo studies were performed using a hemodynamically-validated rodent model of diabetic diastolic heart failure, the diabetic (mRen-2)27 transgenic rat (Ren-2). Urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) was used as a measure of oxidative stress. Results: In- vitro, high glucose (25mmol/l) resulted in increased TxnIP mRNA expression in both neonatal cardiomyocytes as well as H92C cells (2.21 ± 0.6 v 1.00 ± 0.19, p<0.05 compared to normoglycaemic conditions) with a 45% reduction in TRX activity (0.11 ± 0.01 v 0.061± 0.003, p<0.01). In-vivo, diabetes led to a 250% rise in TxnIP mRNA expression compared to control (2.54 ± 0.5 v 1.00 ± 0.11, p<0.001) that was accompanied by a three fold rise in urinary 8-OHdG (680 ± 280 v 1395 ± 391 ng/ml, p<0.001). Conclusion: In both the in vitro and in vivo settings, high glucose leads to TxnIP over-expression associated with reduced TRX activity thereby increasing oxidative stress and implicating this system in the pathogenesis of the cardiac dysfunction that characterizes the diabetic state. Pharmacological manipulation of the TRX-TxnIP system may represent a novel target to reduce diabetic complications.