Abstract 13175: Impaired Activity of The Thioredoxin Reducing System Contributes to Diabetic Cardiac Disease: Evidence from Human and Experimental Studies
Background: Excessive reactive oxygen species (ROS) are implicated in the pathogenesis of diabetes induced vascular complications, including diabetic cardiomyopathy. While increased ROS are traditionally viewed as arising from the metabolic flux of diabetes, we explored the possibility that altered activity of anti-oxidant systems may also contribute, focusing upon the activity of the thioredoxin (TRX) reducing system, and expression of its endogenous inhibitor thioredoxin interacting protein (TxnIP).
Methods: TRX activity, mRNA expression and protein content of its endogenous inhibitor, TxnIP, were examined in human right atrial biopsy specimens from diabetic and non-diabetic individuals obtained during coronary artery bypass surgery (CABG) and in cardiac tissue derived from a hemodynamically validated animal model of diastolic heart failure, the streptozotocin TGR(mRen)2-27 rat. ROS were assessed using 3-nitrotyosine staining.
Results: Right atrial tissue from individuals with diabetes demonstrated a significant increase in TxnIP mRNA expression (>30 fold), and protein (17% increase), relative to tissue from control subjects (P<0.01). This was associated with a 21% reduction in TRX activity (p<0.05). In correlative animal studies, diabetic Ren-2 rats demonstrated a similar increase in TxnIP protein expression (p<0.05), with a 23% reduction in TRX activity (p<0.001). This was associated with a significant increase in ROS as assessed by 3-nitrotyrosine immunoreactivity (p<0.05 when compared with control Ren-2 rats). Diabetic Ren-2 rats demonstrate cardiac hypertrophy, interstitial fibrosis and impaired diastolic function (Tau and the slope of the end-diastolic pressure volume relationship) when compared to non-diabetic controls (all p<0.05).
Conclusion: Increased TxnIP expression and reduced TRX activity occur in cardiac tissue from both patients and animals with diabetes, associated with enhanced oxidative stress. These findings suggest that ROS production in diabetes is not solely the result of metabolic flux, but that impaired thiol reductive capacity, through altered TxnIP expression, also contributes. Enhancing thioredoxin activity may be a novel therapeutic target to reduce diabetic cardiac complications.
- © 2012 by American Heart Association, Inc.