Proteomic inventory of myocardial proteins from patients with chronic Chagas' cardiomyopathy

Abstract

Chronic Chagas' disease cardiomyopathy (CCC) is an often fatal outcome of Trypanosoma cruzi infection, with a poorer prognosis than other cardiomyopathies. CCC is refractory to heart failure treatments, and is the major indication of heart transplantation in Latin America. A diffuse myocarditis, plus intense myocardial hypertrophy, damage and fibrosis, in the presence of very few T. cruzi forms, are the histopathological hallmarks of CCC. To gain a better understanding of the pathophysiology of CCC, we analyzed the protein profile in the affected CCC myocardium. Homogenates from left ventricular myocardial samples of end-stage CCC hearts explanted during heart transplantation were subjected to two-dimensional electrophoresis with Coomassie blue staining; protein identification was performed by MALDI-ToF mass spectrometry and peptide mass fingerprinting. The identification of selected proteins was confirmed by immunoblotting. We demonstrated that 246 proteins matched in gels from two CCC patients. They corresponded to 112 distinct proteins. Along with structural/contractile and metabolism proteins, we also identified proteins involved in apoptosis (caspase 8, caspase 2), immune system (T cell receptor ß chain, granzyme A, HLA class I) and stress processes (heat shock proteins, superoxide dismutases, and other oxidative stress proteins). Proteins involved in cell signaling and transcriptional factors were also identified. The identification of caspases and oxidative stress proteins suggests the occurrence of active apoptosis and significant oxidative stress in CCC myocardium. These results generated an inventory of myocardial proteins in CCC that should contribute to the generation of hypothesis-driven experiments designed on the basis of the classes of proteins identified here.

Proteome Expression and Carbonylation Changes During Trypanosoma cruzi Infection and Chagas Disease in Rats

“…VIM is also shown to be localized in the carotid artery and heart valves and serves as a target antigen of peripheral and heart-infiltrating T cells during valvular disease (63). Increased detection of VIM in the heart is indicative of occurrence of a fibrotic process, as infiltrating fibroblasts replace damaged cardiomyocytes in disease conditions and has been identified by proteomic inventory of myocardial proteins in patients with Chagas disease (64). Results obtained through IPA analysis indicated that VIM modulates NOS2 and is indirectly linked to IL-1␤ and TNF-␣ expression in the disease state.…”

Targeting caspases in intracellular protozoan infections

“…(146)(147)(148) Proteomic and western blot analyses show increased expression and processing of caspase-8 in the hearts of patients with chronic Chagas cardiomyopathy. (149) Caspase-8 might be expressed by myocytes undergoing death or by apoptotic lymphocytes within inflammatory infiltrates, as TCR expression was also detected in the hearts. (149) An issue that remains unclear is how apoptosis or caspase inhibition will affect inflammation and damage in the hearts upon T. cruzi infection.…”

“…(149) Caspase-8 might be expressed by myocytes undergoing death or by apoptotic lymphocytes within inflammatory infiltrates, as TCR expression was also detected in the hearts. (149) An issue that remains unclear is how apoptosis or caspase inhibition will affect inflammation and damage in the hearts upon T. cruzi infection. In the experimental model of Chagas' disease, treatment with a general caspase inhibitor did not affect the extension of inflammatory infiltrates in the hearts, but the death of cardiomyocytes was not assessed.…”

Chagas disease cardiomyopathy: current concepts of an old disease

“…Our group has recently described an inventory of myocardial proteins from patients with severe CCC. This has allowed us to identify proteins with high and low abundance in the tissue, including proteins with structural, metabolic, stress, apoptosis and immune response functions (TEIXEIRA et al, 2006). It would be interesting to investigate whether the expression of cardiac proteins differs between severe CCC patients and mild CCC or IND subjects.…”