SAT-552 Oxidative Stress Induces Type 3 Deiodinase on Multiple Tissues in Disease: Implications to Nonthyroidal Illness Syndrome Pathophysiology

Abstract

Imbalances in the redox status are involved in type 3 deiodinase (D3) induction in the non-thyroidal illness syndrome (NTIS). The mechanisms responsible for D3 dysfunction under systemic redox alterations in disease are poorly understood. Recently, the resemblance of D3 with peroxiredoxin-like proteins has been suggested. Objective: Evaluate the paths of redox alterations leading to D3 induction in liver, muscle, and brain in an animal model of NTIS. Methods: Male Wistar rats submitted to left anterior coronary artery occlusion (MI) were treated or not with N-acetylcysteine (NAC), an antioxidant that replenishes cysteine levels. Ten days post-MI animals were sacrificed and tissues collected. D3 activity was measured in liver, muscle, and brain. Total carbonyl and sulphydryl contents, as well as enzymatic and nonenzymatic oxidative parameters, were determined. Results: Compared to sham, D3 activity was increased in liver (P=0.002), muscle (P=0.03) and brain (P=0.01) in MI-placebo animals. All tissues from placebo group showed increased carbonyls, marker of oxidative damage to protein, and diminished sulphydryl levels, indicating cysteine and thiol consumption (all P=0.001). GSH/GSSG ratio was altered in all tissues (P=0.001). GSH is a critical antioxidant that depends on sulphydryl groups as a ready source of reducing equivalents. Liver and muscle had augmented glutathione peroxidase (GPx), glutathione reductase (GR) and thioredoxin reductase (TRx) levels (P=0.001). NAC prevented all the alterations described above. Conclusion: D3 induction in tissues correlates to MI-induced redox changes. NAC preventing D3 dysfunction indicates a role for altered cysteine/thiol in this process. The enzymatic profile suggests a functional regenerating GSH system. The set of these results adds to the present knowledge of NTIS physiopathology since they indicate a reversible oxidative post-transcriptional modification of D3 probably through a putative formation of mixed disulfides with cysteine and glutathione (glutathionylation process) that could be reduced by TRx as one of the causes for D3 induction in disease. The possibility that the thiols are being consumed to form disulphide bonds from augmented GSSG could also be considered. Antioxidant treatment prevents D3 dysfunction in multiple tissues, which probably contribute to avoiding NTIS.