Molecular Signature of Nitroso–Redox Balance in Idiopathic Dilated Cardiomyopathies

BACKGROUND: Idiopathic dilated cardiomyopathy is one of the most common types of cardiomyopathy. It has been proposed that an increase in oxidative stress in heart failure leads to a decrease in nitric oxide signaling, leading to impaired nitroso–redox signaling. To test this hypothesis, we investigated the occurrence of protein S-nitrosylation (SNO) and oxidation in biopsies from explanted dilated cardiomyopathy and nonfailing donor male and female human hearts. METHODS AND RESULTS: Redox-based resin-assisted capture for oxidation and SNO proteomic analysis was used to measure protein oxidation and SNO, respectively. In addition, 2-dimensional difference gel electrophoresis using maleimide sulfhydryl-reactive fluors was used to identify the SNO proteins. Protein oxidation increased in dilated cardiomyopathy biopsies in comparison with those from healthy donors. Interestingly, we did not find a consistent decrease in SNO in failing hearts; we found that some proteins showed an increase in SNO and others showed a decrease, and there were sex-specific differences in the response. We found 10 proteins with a significant decrease in SNO and 4 proteins with an increase in SNO in failing female hearts. Comparing nonfailing and failing male hearts, we found 9 proteins with a significant decrease and 12 proteins with a significant increase. We also found an increase in S-glutathionylation of endothelial nitric oxide synthase in failing female versus male hearts, suggesting an increase in uncoupled nitric oxide synthase in female hearts. CONCLUSION: These findings highlight the importance of nitroso–redox signaling in both physiological and pathological conditions, suggesting a potential target to treat heart failure.