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 (P<0.01). Nitrotyrosine content of cardiomyocytes was markedly reduced in rhTrx-treated animals (P<0.01). 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 microM for 3 h) resulting in a nitrotyrosine content comparable to that seen in the ischemic/reperfused heart and causing significant cardiomyocyte apoptosis (P<0.01). Treatment with rhTrx markedly decreased SIN-1 induced apoptosis (P<0.01).

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.

• Authors: L Tao, E Gao, A Hu, C Coletti, Y Wang, T A Christopher, B L Lopez, W Koch, X L Ma
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 149 Issue 3 Pg. 311-8 (Oct 2006) ISSN: 0007-1188 [Print] England
• PMID: 16921396 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Superoxides
• Peroxynitrous Acid
• Nitric Oxide
• 3-nitrotyrosine
• Tyrosine
• Thioredoxins
• linsidomine
• Molsidomine

Topics

• Animals
• Apoptosis (drug effects)
• Male
• Mice
• Molsidomine (analogs & derivatives, pharmacology)
• Myocardial Ischemia (drug therapy, pathology)
• Myocardium (pathology)
• Myocytes, Cardiac (drug effects, pathology)
• Nitric Oxide (biosynthesis)
• Oxidative Stress (drug effects)
• Peroxynitrous Acid (metabolism)
• Superoxides (metabolism)
• Thioredoxins (pharmacology)
• Tyrosine (analogs & derivatives, analysis)