Abstract
Background: DJ-1 is a cytoprotective protein expressed in the heart. It can act as an antioxidant in oxidative stress conditions where it is cleaved and converted into an active protease. DJ-1 and Thioredoxin (Trx1), another antioxidant, are known to act on related targets, both playing a role in opposing the apoptosis signaling kinase 1 (ASK1) signaling pathway. We recently found that the cleaved form of DJ-1 attenuates ischemia-reperfusion (I/R)-induced heart failure by reducing glycative stress. Thus, the purpose of this study was to examine the role of DJ-1’s antiglycation activity on Trx1 and how this effects the ASK1 signaling pathway after I/R injury. Methods and Results: Initial studies found that DJ-1 deficient mice (DJ-1 KO) showed decreased levels of Trx1 activity after I/R injury compared to wild-type control mice. To explore a possible explanation for this decrease, we assessed the glycation of Trx1. Analysis revealed higher levels of carboxymethyl-lysine (CML) glycation of Trx1 in hearts of DJ-1 KO mice after I/R injury. This was accompanied by an increase in ASK1 phosphorylation and activity, as well as an increase in the phosphorylation of JNK, a downstream target of ASK1. To further determine if DJ-1 directly influences this signaling cascade, we employed an adenoviral approach (AAV9-CMV-DJΔc) to over-express the cleaved form of DJ-1. Compared to mice treated with a control virus, the overexpression of cleaved DJ-1 decreased the glycation of Trx1. Further, Trx1 activity was increased and ASK1 signaling was attenuated. Conclusion: These data suggest that the antiglycation activity of DJ-1 plays a role in preserving Trx1 activity after I/R injury. By expanding our perspective of how DJ-1 interacts with Trx1, these data bring us closer to uncovering a therapy that targets the ASK1 signaling pathway in the heart.
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