Abstract 1689: Thioredoxin Prevents Oxidative Stress Induced by Diabetes Mellitus
Hyperglycemia induces oxidative stress and contributes to the pathologic changes in diabetic hearts. Thioredoxin1 (Trx1) is a 12-kDa multifunctional protein with redox-sensitive cysteine residues and acts as an antioxidant in cells. Our previous study demonstrated that inhibition of endogenous thioredoxin1 in the heart increases oxidative stress and cardiac hypertrophy. Since thioredoxin1 provides cellular protection against oxidative stress, in this study, we hypothesized that cardioprotective action of thioredoxin1 could decrease the oxidative stress and modify pathophysiological changes in the hearts of diabetic mice. Ten to twelve months old genetically engineered mice with cardiac specific overexpression of Trx1 and littermate wild type (WT) mice were injected with streptozotocin (180 mg/kg) intraperitoneally and studied after 3 months of induction of diabetes mellitus (DM). Mice with blood sugar above 300 mg/dl were considered diabetic for this study. Left ventricular (LV) ejection fraction (LVEF) was significantly higher in Trx1 DM (80±1%, n=9) compared with WT DM (72±3%, n=5) mice, p<0.05. There was no difference in the LV size, as assessed by LV/body weight (LV/BW) between any of the groups. Apoptosis, as quantitated by TUNEL, was significantly increased, p<0.05, in WT DM (0.1±0.01%) compared to WT C (0.04±0%) mice. Apoptosis was also significantly higher, p<0.05, in the Trx1 DM (0.06±0%) compared with Trx1 control (Trx1 C) and WT C mice (both 0.04±0%). However, apoptosis in Trx1 DM mice was significantly less compared with WT DM mice, p<0.01. Protein kinase C (PKC) epsilon activity was significantly higher, p<0.01, in the membrane fraction of WT DM (29.6±1.1) compared with WT C (23.5± 0.8), Trx1 C (24.3±0.4), and Trx1 DM (22.5±0.7) mice. There was no significant difference in the PKC delta activity between any of the groups. Catalase and superoxide dysmutase (SOD) expression was significantly higher (p<0.01) in WT DM compared with WT C, Trx C, and Trx1 DM mice. These results indicate that overexpression of thioredoxin1 protects the heart from apoptosis, decreases the markers of oxidative stress, and improve cardiac function in diabetic mice.