Thioredoxin reduces post‐ischemic myocardial apoptosis by reducing oxidative/nitrative stress

Abstract

Background and purpose: Thioredoxin (Trx) is an oxidoreductase that prevents free radical-induced cell death in cultured cells. Here we assessed the mechanism(s) underlying the cardioprotective effects of Trx in vivo. Experimental approach: The effects of myocardial ischemia (30 min) and reperfusion were measured in mice, with assays of myocardial apoptosis, superoxide production, NOx and nitrotyrosine content, and myocardial infarct size. Recombinant human Trx (rhTrx, 0.7-20 mg kg -1 , i.p.) was given 10 min before reperfusion. Key results: Treatment with 2 mg kg -1 rhTrx significantly decreased myocardial apoptosis and reduced infarct size (Po0.01). Nitrotyrosine content of cardiomyocytes was markedly reduced in rhTrx-treated animals (Po0.01). To further identify the mechanisms by which rhTrx may exert its anti-nitrative effect, iNOS expression and production of NOx and superoxide were determined. Treatment with rhTrx had no significant effect on iNOS expression or NOx content in the ischemic/reperfused heart. However, it markedly upregulated mSOD and reduced tissue superoxide content. To further establish a causative link between the anti-peroxynitrite effect and the cardioprotective effect of rhTrx, cultured adult cardiomyocytes were incubated with SIN-1, a peroxynitrite donor, (50 mM for 3 h) resulting in a nitrotyrosine content comparable to that seen in the ischemic/ reperfused heart and causing significant cardiomyocyte apoptosis (Po0.01). Treatment with rhTrx markedly decreased SIN-1 induced apoptosis (Po0.01). Conclusions and implications:These results demonstrate that Trx is a novel anti-apoptotic and cardioprotective molecule that exerts its cardioprotective effects by reducing ischemia/reperfusion-induced oxidative/nitrative stress.

Regulation of the Catalytic Activity and Structure of Human Thioredoxin 1 via Oxidation and S-Nitrosylation of Cysteine Residues

“…A similar preserving role for the intramolecular two disulfide formation between Cys 62 and Cys 69 is also possible. A recent study showed that hTrx1 expression reduces the tissue content of nitrotyrosine, which is an indirect determinant of in vivo ONOO Ϫ production and an index of nitrative stress (55). In another study it is suggested that hTrx1 can be nitrated on Tyr 49 , which leads to irreversible inhibition of its redox regulatory activity (56).…”

Thioredoxin Activates MKK4-NFκB Pathway in a Redox-dependent Manner to Control Manganese Superoxide Dismutase Gene Expression in Endothelial Cells

“…We have previously reported that Trx is internalized into A549 and MCF-7 cells (4,54). Furthermore, injected Trx has been shown to be internalized by cardiomyocytes and brain cells (40,55,56). As of today, no cell surface receptor has been discovered for Trx.…”

Adiponectin Cardioprotection After Myocardial Ischemia/Reperfusion Involves the Reduction of Oxidative/Nitrative Stress

“…21,26 After demonstration of production of NO and · O 2 Ϫ, the 2 free radicals that react at a diffusion-limited rate to form the highly cytotoxic molecule peroxynitrite, we then tested a hypothesis that lack of adiponectin may increase peroxynitrite formation, and thus render cardiomyocytes more susceptible to I/R injury. Consistent with our previous findings, I/R resulted in significant peroxynitrite production as evidenced by a Ͼ2.3-fold increase in nitrotyrosine content in the I/R cardiac tissue.…”