Abstract 1292: Functional Relevance of Mitochondrial Thioredoxin Reductase After Myocardial Ischemia and Reperfusion in vivo
Myocardial ischemia and reperfusion (I/R) results in increased generation of reactive oxygen species (ROS) and increased cell death. Cardiac tissue-restricted ablation of mitochondrial thioredoxin reductase (TrxR2) results in fatal dilated cardiomyopathy (Conrad et al, 2004). To study the relevance of the adult TrxR2 after myocardial I/R, tamoxifen-inducible cardiospecific TrxR2-deficient mice were generated (TrxR2-/lox(Tg[αMHC-MERCreMER]), KO). TrxR2=/ lox,(Tg[αMHC-MERCreMER]) served as control (WT).
Methods: All animals received tamoxifen for 5 weeks following 4 weeks with regular food. Knock-down of the target gene was confirmed with RT-PCR after this time period in selected animals. After 90 minutes LAD-occlusion followed by 24 hours (Group 1, n=8 per group) or 14 days (Group 2, n=7 per group) reperfusion left ventricular function was invasively analysed at rest as well as after infusion of increasing concentration of norepinephrine (NE) using millar tip catheter. Furthermore infarct size (% of left ventricle) was assessed planimetrically after histological staining (8 slices per animal) ex vivo.
Results: Electron beam microscopy revealed a larger extent of mitochondrial disintegration 24h after I/R. At this time point, left ventricular developed pressure (LVDP) was significantly impaired in KO animals (71,6±3mmHg) compared to WT controls (82,3±2mmHg). At d14 of I/R, in baseline measurement LVDP was similarly depressed in KO and WT animals (77±3 vs. 78±3mmHg) compared to sham operated animals (98±5mmHg). However, reserve function was significantly increased in WT (136±5mmHg at 100ng/10μl NE ) compared to KO (111±5mmHg). Notably, an increase of LV-infarction was found in KO animals (25±2,5%) compared to WT-controls (19±1,3%). We conclude, that mitochondrial thioredoxin reductase plays an instrumental role in detoxifying mitochondrial ROS after myocardial ischemia and reperfusion in vivo.