Protein 3-nitrotyrosine formation during Trypanosoma cruzi infection in mice

Nitric oxide ((NO)-N-center dot) is a diffusible messenger implicated in Trypanosoma cruzi resistance. Excess production of (NO)-N-center dot and oxidants leads to the generation of nitrogen dioxide ((NO2)-N-center dot), a strong nitrating agent. Tyrosine nitration is a post-translational modification resulting from the addition of a nitro (-NO2) group to the ortho-position of tyrosine residues. Detection of protein 3-nitrotyrosine is regarded as a marker of nitro-oxidative stress and is observed in inflammatory processes. The formation and role of nitrating species in the control and myocardiopathy of T. cruzi infection remain to be studied. We investigated the levels of (NO)-N-center dot and protein 3-nitrotyrosine in the plasma of C3H and BALB/c mice and pharmacologically modulated their production during the acute phase of T cruzi infection. We also looked for protein 3-nitrotyrosine in the hearts of infected animals. Our results demonstrated that C3H animals produced higher amounts of (NO)-N-center dot than BALB/c mice, but their generation of peroxynitrite was not proportionally enhanced and they had higher parasitemias. While N-G-nitroarginine methyl ester treatment abolished (NO)-N-center dot production and drastically augmented the parasitism, mercaptoethylguanidine and guanidoethyl disulfide, at doses that moderately reduced the (NO)-N-center dot and 3-nitrotyrosine levels, paradoxically diminished the parasitemia in both strains. Nitrated proteins were also demonstrated in myocardial cells of infected mice. These data suggest that the control of T. cruzi infection depends not only on the capacity to produce (NO)-N-center dot, but also on its metabolic fate, including the generation of nitrating species that may constitute an important element in parasite resistance and collateral myocardial damage.