Abstract
Recent studies suggested that sestrin2 is a crucial modulator for the production of reactive oxygen species (ROS). In addition, sestrin2 may also regulate ribosomal protein S6 (RpS6), a molecule important for protein synthesis, through the effect of mammalian target of rapamycin (mTOR) complex that is pivotal for longevity. However, the roles of sestrin2 in cerebral ischemia, in which oxidative stress is one of the major pathogenic mechanisms, are still less understood. In this study, we hypothesized that sestrin2 may protect hippocampal CA1 neurons against transient global ischemia (TGI)-induced apoptosis by regulating RpS6 phosphorylation in rats. We found that sestrin2 expression was progressively increased in the hippocampal CA1 subfield 1–48 h after TGI, reaching the maximal level at 24 h, and declined thereafter. Further, an increased extent of RpS6 phosphorylation, but not total RpS6 protein level, was observed in the hippocampal CA1 subfield after TGI. The sestrin2 siRNA, which substantially blocked the expression of TGI-induced sestrin2, also abolished RpS6 phosphorylation. TGI with reperfusion may induce oxidative stress with the resultant formation of 8-hydroxy-deoxyguanosine (8-OHdG). We found that sestrin2 siRNA further augmented the formation of 8-OHdG induced by TGI with reperfusion for 4 h. Consistently, sestrin2 siRNA also enhanced apoptosis induced by TGI with reperfusion for 48 h based on the analysis of DNA fragmentation by agarose gel electrophoresis, DNA fragmentation sandwich ELISA, and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. Together these findings indicated that TGI-induced sestrin2 expression contributed to RpS6 phosphorylation and neuroprotection against ischemic injury in the hippocampal CA1 subfield.
Highlights
Sestrins belong to a family of highly conserved proteins initially discovered as p53-inducible proteins and are believed to protect cells against various insults [1]
We first examined whether sestrin2 was induced by transient global ischemia (TGI) in the hippocampal CA1 subfield
Protein immunoblot showed an evident increase of sestrin2 expression in the hippocampal CA1 subfield 1–48 h after TGI, reaching the maximal level at 24 h (Figure 1A)
Summary
Sestrins belong to a family of highly conserved proteins initially discovered as p53-inducible proteins and are believed to protect cells against various insults [1]. In an experimental model of acute stroke, sestrin was highly induced in the cortical area based on the histological study, suggesting a potentially important role of sestrin in the ischemic brain [1]. These results may denote the pivotal role of sestrin in tissues under ischemic or hypoxic conditions that may be worthy of further exploration. We investigated the hypothesis that the sestrin signaling pathway plays a protective effect in the hippocampal CA1 subfield in transient global ischemia (TGI)/reperfusion through the regulation of RpS6 phosphorylation
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