Redox-sensitive prosurvival and proapoptotic protein expression in the myocardial remodeling post-infarction in rats

Abstract

In this study, we investigated the oxidative stress influence in some prosurvival and proapoptotic proteins after myocardial infarction (MI). Male Wistar rats were divided in two groups: Sham-operated (control) and MI. MI was induced by left coronary artery occlusion. 28-days after surgery, echocardiographic, morphometric, and hemodynamic parameters were evaluated. Redox status (reduced to oxidized glutathione ratio, GSH/GSSG) and hydrogen peroxide levels (H(2)O(2)) were measured in heart tissue. The p-ERK/ERK, p-Akt/Akt, p-mTOR/mTOR and p-GSK-3beta/GSK-3beta ratios, as well as apoptosis-inducing factor (AIF) myocardial protein expression were quantified by Western blot. MI group showed an increase in cardiac hypertrophy (23%) associated with a decrease in ejection fraction (38%) and increase in left ventricular end-diastolic pressure (82%) when compared to control, characterizing ventricular dysfunction. Redox status imbalance was seen in MI animals, as evidenced by the decrease in the GSH/GSSG ratio (30%) and increased levels of H(2)O(2) (45%). This group also showed an increase in the ERK phosphorylation and a reduction of Akt and mTOR phosphorylation when compared to control. Moreover, we showed a reduction in the GSK-3beta phosphorylation and an increase in AIF protein expression in MI group. Taken together, our results show increased H(2)O(2) levels and cellular redox imbalance associated to a higher p-ERK and AIF immunocontent, which would contribute to a maladaptive hypertrophy phenotype.

T3 and T4 decrease ROS levels and increase endothelial nitric oxide synthase expression in the myocardium of infarcted rats

“…Much evidence suggests the involvement of reactive oxygen species (ROS) in the impairment of cardiac function found in the post-infarction period [2,3]. High levels of ROS are correlated with dilatation of the cardiac chambers and with an increase in left ventricle end-diastolic pressure after ischaemic injury [4]. Two important antioxidant defences against ROS in the heart are the thioredoxin (TRX) and glutaredoxin (GRX) systems [5].…”

The role of reactive oxygen species in the pathophysiology of cardiovascular diseases and the clinical significance of myocardial redox

“…Moreover, in a model of heart failure, it has been demonstrated that the activation of MAPK, specifically of p38 MAP kinase, may be an initial step that could lead or it is closely connected to ROS overproduction (13). Thus, ROS could oxidize the myofibrillar proteins, resulting in contractile dysfunction observed in heart failure (14). …”

“…It has been demonstrated that ROS, or more correctly the redox imbalance observed in rat MI model, are related to a decrease in Akt and mTOR phosphorylation, supposing that this could also contribute to molecular and structural abnormalities observed after MI (14). Apart from the mechanisms mediating coronary artery occlusion, ROS play a vital role in the injury following MI.…”

“…Furthermore, ERK signaling has been suggested as one of the responsible pathways involved in the progression from cardiac hypertrophy to heart failure (14). Additionally, the source of oxidant and antioxidant enzyme activities in the right ventricle (RV) and left ventricle (LV) of human failing hearts were investigated, and a significant increase in superoxide production especially by NADPH oxidase in both failing ventricles was found (35).…”

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). Furthermore, norepinephrine-induced apoptosis of rat neonatal cardiomyocytes was shown to involve ROS-mediated inhibition of Akt signaling (Fu et al 2006), suggesting that Akt may confer cardioprotective actions.…”