Redox status and pro‐survival/pro‐apoptotic protein expression in the early cardiac hypertrophy induced by experimental hyperthyroidism

Abstract

This study was conducted to analyse the redox status and redox-sensitive proteins that may contribute to a non-genomic mechanism of cardiac hypertrophy induction by hyperthyroidism. Wistar rats, treated with L-thyroxine (T4) during 2 weeks (12 mg·l(-1) in drinking water), presented cardiac hypertrophy (68% higher than control), without signals of liver or lung congestion. Myocardial reduction of the reduced glutathione: oxidized glutathione (GSSG) ratio (45%) (redox status) and elevation in hydrogen peroxide concentration (H(2) O(2) ) (28%) were observed in hyperthyroid as compared with the control. No significant difference was found in thioredoxin (Trx), Trx reductase activity and Nrf2 (a transcriptional factor) protein expression between groups. Redox-sensitive proteins, quantified using Western blot, presented the following results: increased p-ERK: total extracellular-regulated kinase (ERK) (200%) and Bax:Bcl-2 (62%) ratios and reduced total-Akt (63%) and p-Akt (53%) expressions in the hyperthyroid rats as compared with the control. The redox imbalance, associated with increased immunocontent of a protein related to maladaptative growth (ERK) and reduced immunocontent of protein related to cytoprotection/survival (Akt), may suggest that the molecular scenario could favour the decompensation process of cardiac hypertrophy induced by experimental hyperthyroidism.

Reactive Oxygen Species (ROS) Signaling in Cardiac Remodeling and Failure

“…Interestingly, doxorubicin-induced cardiotoxicity was exacerbated in transgenic mice overexpressing Nrdp1 via enhanced ROS-mediated inhibition of Akt signaling (Zhang et al 2011b), while cardiac hypertrophy in a rat model of experimental hyperthyroidism was associated with increased H 2 O 2 activity generation and downregulation of the Akt pathway (Fernandes et al 2011). Similarly, elevated ROS production in rats subjected to chronic MI was accompanied by decreased phosphorylation of both Akt and GSK-3b in association with significant cardiac hypertrophy and contractile dysfunction (Schenkel et al 2010).…”

Role of Oxidative Stress in Thyroid Hormone-Induced Cardiomyocyte Hypertrophy and Associated Cardiac Dysfunction: An Undisclosed Story

“…THs have also been proposed to act through a nongenomic mechanism, which can occur rather rapidly through binding to a membrane receptor to activate signaling. Thus, cardiac hypertrophy/dysfunction could also be the result of activating signaling pathways through such nongenomic mechanisms where oxidative stress and ROS may serve as potential modulators of this response in hyperthyroidism [22, 24, 42]. …”

“…Conversely, cardiac GPx activity was found to decrease in the hearts of old but not young hyperthyroid rats [45]. On the other hand, Fernandes et al found no significant differences in the cardiac Trx or GSH activities after 2-week treatment of T4 [24]; yet, the same group reported increased Trx [22] but decreased GSH [18–20, 22] activities in the hyperthyroid hearts after 4-week treatment in the same model. Additionally, it was reported that T4 [26] but not T3 [48, 53] decreases the cardiac GR activity.…”

“…Indeed, depressed cardiac contractility and enhanced apoptosis have been proposed to result in heart failure in hypertrophied myocardium following hyperthyroidism [94]. Recently, induction of apoptosis-related signaling has been coupled to increased oxidative stress in the hyperthyroid hearts [24]. …”

“…In hyperthyroid rats that revealed cardiac hypertrophy and ventricular dysfunction after 4-week treatment of T4, Araujo et al showed that oxidative stress in the myocardium induces adaptations in the GPx-GR and Trx-Prx systems through Nrf-2 activation [22] (Figure 3). Conversely, the same group showed that this pathway was not collaborating with the maintenance of redox balance after 2-week treatment of T4, when the same rats exhibited cardiac hypertrophy but preserved cardiac function [24]. In addition to its role in keeping redox homeostasis, Trx has also been involved in the repression of ROS-mediated pathological cardiac hypertrophy, signifying a cardioprotective action, as well as in the regulation of the cell survival pathway [100, 101].…”