Selenoprotein T (SelT) is a thioredoxin-like protein, which is abundantly but transiently expressed in the heart during the embryonic development, suggesting that SelT plays a limited role during adulthood. However, data from our laboratory show that cardiac SelT expression increases after myocardial infarction. This suggests that SelT may play a yet unrevealed role in cardiovascular diseases but SelT’s potential protective role is unknown. Thus, we sought to investigate the cardiac effects of a SelT-mediated therapy in chronic heart failure (CHF) using either a protein or gene therapy through either a protein supplementation, or rAAV encoding for different forms of SelT. SelT supplementation (15μg/kg/day, IP, administered for 1 month starting 7 days after MI) resulted in a restoration of cardiac output and LV fractional shortening (sham: 178,1±14,8; MI: 161,1±7,7; MI+SelT; 177,6 ±8,0 and sham: 44,5±5,1; MI: 17,1±0,8; MI+SelT: 25,6±2,4, respectively), in association with an improvement of LV end-diastolic and end-systolic pressures as well as LV tissue perfusion. These changes were associated with a lower oxidative status and with a decrease in inflammation pathways (-32,7% vs MI for oxidative stress and - 27,2% and - 31,4% for inflammation, measured by electron paramagnetic resonance and western blotting analyses of IL1ß and IL6 expressions, respectively). All these effects were observed at identical infarct sizes. In parallel, a single intravenous injection of rAAV9-SelT (1.1011 virus - genome copies) one week after MI resulted in an increased cardiac SelT expression 3 weeks after injection (+150%, p<0.05). This SelT - overexpression reduced HF-induced increase in left ventricular diameters in both systole and diastole (at 1 and 3 months post-MI). Simultaneously, SelT improved stroke volume and cardiac output, without change in heart rate or body weight. Moreover, cardiac perfusion was improved by rAAV9-SelT in both interventricular septum and in the border zone of the infarct. These changes were associated with an improvement in cardiac compliance and elastance parameters assessed by invasive pressure/volume curves (compliance: sham: 18.2 ±1.5; HF: 11.0±1.0; HF+rAAV9-SelT: 15.3±0.5 and elastance: sham: 1.3±0.2; HF: 2.8±0.2; HF+rAAV9-SelT: 1.4±0.2, respectively; p<0.05 vs. HF). The third part of this project consisted in a single intramuscular injection of rAAV8-SelT (1.1011 virus-genome copies, 7 days after CAL) of either the normal form (rAAV8-SelTSec), either the modified form in which the Sec residue is replaced by an Ala (rAAV8-SelTAla). rAAV8-SelTSec administration resulted in a significant increase in cardiac SelT levels as soon as 3 weeks post-administration. After 3 months, SelTSec reduced LV dilation and restored cardiac output. Simultaneously SelT improved both LV elastance and compliance. In contrast, administration of the rAAV8-SelTAla did not modify the CHF-related cardiac dysfunction, suggesting that the selenocysteine residue is essential to the normal protein function. Our results clearly show that increasing SelT to supra-normal levels reduces CHF-induced cardiac dysfunction through a selenium-dependent pathway. These results suggest that SelT might be a promising therapeutic option in the treatment of CHF.