Ischemic postconditioning confers cardioprotection and prevents reduction of Trx-1 in young mice, but not in middle-aged and old mice

Abstract

Thioredoxin-1 (Trx-1) is part of an antioxidant system that maintains the cell redox homeostasis but their role on ischemic postconditioning (PostC) is unknown. The aim of this work was to determine whether Trx-1 participates in the cardioprotective mechanism of PostC in young, middle-aged, and old mice. Male FVB young (Y: 3 month-old), middle-aged (MA: 12 month-old), and old (O: 20 month-old) mice were used. Langendorff-perfused hearts were subjected to 30 min of ischemia and 120 min of reperfusion (I/R group). After ischemia, we performed 6 cycles of R/I (10 s each) followed by 120 min of reperfusion (PostC group). We measured the infarct size (triphenyltetrazolium); Trx-1, total and phosphorylated Akt, and GSK3β expression (Western blot); and the GSH/GSSG ratio (HPLC). PostC reduced the infarct size in young mice (I/R-Y: 52.3 ± 2.4 vs. PostC-Y: 40.0 ± 1.9, p < 0.05), but this protection was abolished in the middle-aged and old mice groups. Trx-1 expression decreased after I/R, and the PostC prevented the protein degradation in young animals (I/R-Y: 1.05 ± 0.1 vs. PostC-Y: 0.52 ± .0.07, p < 0.05). These changes were accompanied by an improvement in the GSH/GSSG ratio (I/R-Y: 1.25 ± 0.30 vs. PostC-Y: 7.10 ± 2.10, p < 0.05). However, no changes were observed in the middle-aged and old groups. Cytosolic Akt and GSK3β phosphorylation increased in the PostC compared with the I/R group only in young animals. Our results suggest that PostC prevents Trx-1 degradation, decreasing oxidative stress and allowing the activation of Akt and GSK3β to exert its cardioprotective effect. This protection mechanism is not activated in middle-aged and old animals.

Role of thioredoxin-1 in ischemic preconditioning, postconditioning and aged ischemic hearts

“…Our findings evidenced an increase in the infarct size only in old mice (20 month old), but we did not observe changes in the infarct size in middle-aged mice (12 month old). In this study we also demonstrated that PostC protocol did not confer protection in the middle-aged (12 month old) and in the old mice (>18 month old) [68]. These data are according with our finding that showed that Trx-1 levels in normoxic conditions, decreased in middle-age and old mice, compared with young mice (Fig.…”

“…At least to our knowledge, we were the first to suggest a role for Trx-1 in PostC [68]. In isolated and perfused mice heart, we demonstrated that PostC decreases the infarct size in young mice, as we expected, and this cardioprotection was abolished in middle-aged and old mice.…”

“…The reduction of infarct size in PostC is in concordance with Trx-1 levels preservation and with an improvement in the GSH/GSSG ratio (oxidative stress) in comparison to the I/R control group. Also, this cardioprotection was accompanied by the Akt activation and the phosphorylation and inhibition of GSK3␤ 25 , both proteins related to cell survival pathway [68]. Therefore, our data suggests that the preservation of Trx-1 levels in young mice subjected to a PostC protocol would reduce oxidative stress and allow the RISK signaling pathway (Akt-GSK3␤) activation to increase cell survival (Fig.…”

Modulation of signaling mechanisms in the heart by thioredoxin 1

“…Furthermore, in young mice, ischemic postconditioning conferred a protective phenotype after I/R by preventing Trx1 degradation and, thus, increasing Akt and GSK-3β phosphorylation. However, the postconditioning effect was abolished in middle-aged and older mice, as Trx1 was degraded rapidly [64, 65]. This suggests that Trx1 plays an important role in mediating the cardioprotection afforded by ischemic postconditioning.…”

Impaired RISK-GSK3β Pathway is Responsible for Comorbidities by Suppressing the Conditioning Cardioprotection

“…On the contrary, aging suppressed the conditioning protection due to insulin insensitiveness and overexpression of PHLPP-1(a specific negative regulator of Akt) during myocardial IRI, which subsequently limited Akt activity in the aged heart (27). In addition, a new study reported that ischemic postconditioning (IPostC) failed to exert its cardioprotective effect owing to thioredoxin-1 degradation, a part of antioxidant system, and subsequently inactivated the Akt and GSK3β in middle-aged and old animals (28). In addition to the impact of the Akt pathway, the aging also affects the ERK1/2 state in the situation of IRI.…”