Selenium deficiency-induced thioredoxin suppression and thioredoxin knock down disbalanced insulin responsiveness in chicken cardiomyocytes through PI3K/Akt pathway inhibition

Publication date: October 2017
Source:Cellular Signalling, Volume 38
Author(s): Jie Yang, Sattar Hamid, Jingzeng Cai, Qi Liu, Shiwen Xu, Ziwei Zhang
Thioredoxin (Txn) system is the most crucial antioxidant defense mechanism in cell consisting of Txn, thioredoxin reductase (TR) and Nicotinamide Adenine Dinucleotide Phosphate (NADPH). Perturbations in Txn system may compromise cell survival through oxidative stress induction. Metabolic activity of insulin plays important roles in fulfilling the stable and persistent demands of heart through glucose metabolism. However, the roles of Txn and Txn system in insulin modulated cardiac energy metabolism have been less reported. Therefore, to investigate the role of Txn in myocardial metabolism, we developed a Se-deficient chicken model (0.033mg/kg) for in-vivo and Txn knock down cardiomyocytes culture model (siRNA) for in-vitro studies. Quantitative real time PCR and western blotting was performed. Se deficiency suppressed Txn and TR in cardiac tissues. Significant increases in ROS (P<0.05) levels signify the onset of oxidative stress and in both models. Se deficiency-induced Txn suppression model and Txn knock down cardiomyocytes models significantly decreased (P<0.05), the mRNA and protein levels of insulin-like growth factors (IGF1, IGF2), IGF-binding proteins (IGFBP2, IGFBP4), insulin receptor (IR), insulin receptor substrates (IRS1, IRS2), and glucose transporters (GLUT1, GLUT3, GLUT8), however, IGFBP3 expression increased in Txn knock down cardiomyocytes. In addition, in contrast to their respective controls, Se deficiency-induced Txn depleted tissues and Txn deleted cardiomyocytes showed suppression in mRNA and protein levels of PI3K, AKT, P-PI3K, and repression in FOX, P-FOX JNK genes. Combing the in vitro and in vivo experiments, we demonstrate that Txn gene suppression can cause dysfunction of insulin-modulated cardiac energy metabolism and increase insulin resistance through PI3K-Akt pathway inhibition. Herein, we conclude that inactivation of Txn system can alter cellular insulin response through IRS/PI3K/Akt pathway repression and JNK and FOX expression. These findings point out that Txn system can redox regulate the insulin dependent glucose metabolism in heart and is essential for cell vitality. Moreover, the increased expression of IGFBP3 indicates that it can be a potential negative modulator of metabolic activity of insulin in Txn deficient cells.

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