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Abstract
Chagas disease is initiated upon infection by Trypanosoma cruzi. Among the health consequences is a decline in heart function, and the pathophysiological mechanisms underlying this manifestation are not well understood. To explore the possible mechanisms, we employed IgY LC10 affinity chromatography in conjunction with ProteomeLab PF2D and two-dimensional gel electrophoresis to resolve the proteome signature of high and low abundance serum proteins in chagasic patients. MALDI-TOF MS/MS analysis yielded 80 and 14 differentially expressed proteins associated with cardiomyopathy of chagasic and other etiologies, respectively. The extent of oxidative stress-induced carbonyl modifications of the differentially expressed proteins (n = 26) was increased and coupled with a depression of antioxidant proteins. Functional annotation of the top networks developed by ingenuity pathway analysis of proteome database identified dysregulation of inflammation/acute phase response signaling and lipid metabolism relevant to production of prostaglandins and arachidonic acid in chagasic patients. Overlay of the major networks identified prothrombin and plasminogen at a nodal position with connectivity to proteome signature indicative of heart disease (i.e., thrombosis, angiogenesis, vasodilatation of blood vessels or the aorta, and increased permeability of blood vessel and endothelial tubes), and inflammatory responses (e.g., platelet aggregation, complement activation, and phagocyte activation and migration). The detection of cardiac proteins (myosin light chain 2 and myosin heavy chain 11) and increased levels of vinculin and plasminogen provided a comprehensive set of biomarkers of cardiac muscle injury and development of clinical Chagas disease in human patients. These results provide an impetus for biomarker validation in large cohorts of clinically characterized chagasic patients.
Highlights
From the ‡Department of Microbiology and Immunology, the Faculty of the Institute for Human Infections and Immunity, Center for Tropical Diseases, and the Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas 77555-1070, the §Instituto de Patología Experimental, Consejo Nacional de Investigaciones Científicas y Tecnicas-Universidad Nacional de Salta, Salta CP: 4400, Argentina, and the ¶Servicio de Cardiología, Hospital San Bernardo, Salta CP: 4400, Argentina
PF2D/Mass Spectrometric Analysis of Serum Proteomic Signature of Low Abundance Proteins in Chagasic Patients—We examined the reproducibility of the PF2D system by submitting enriched sera samples from normal healthy subjects to first dimension high performance chromatofocusing on different days and submitted triplicates of first dimension fractions for second dimension reverse phase (RP)-HPLC analysis
We have developed a comprehensive serum proteome profile of chagasic human patients by utilizing a combination of PF2D ProteomeLab and traditional 2D-GE techniques
Summary
In chronic conditions or disease states, as is noted in chagasic patients [5, 6], modification of the proteome manifests as a result of disease-associated changes in specific genes up- or down-regulation, isoform switching, or de novo protein synthesis [7, 8]. Progression of disease severity, presented by an increasing order of cardiac injury and cell death [9, 10], may result in the release of intracellular proteins in the peripheral system, altering the proteome profile. Serum Proteomic Signature in Chagasic Patients that reactive oxygen species (ROS) of inflammatory and mitochondrial origin contribute to oxidative modification of proteins in peripheral blood and myocardium [11,12,13,14]. Proteomic examples of oxidative modification identification in cardiovascular diseases are lacking
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