MODIFICATION OF CARDIOVASCULAR PROTEINS BY METABOLIC DISEASE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Unfavorable metabolic conditions and diseases, including obesity, diabetes, and hyperlipidemia, are major causes for cardiovascular disease in the Western world, and yet the early detection and monitoring of the adverse effects of metabolic disease on the heart and vasculature remain elusive. Inflammation, oxidative stress, enhanced accumulation of lipids, and lipid peroxidation in the heart and vasculature are at the root of diastolic heart failure, hypertension, and cardiac and vascular hypertrophy, stiffening, and dysfunction. Somewhat stereotypical, nonspecific changes do occur in plasma protein indicators of inflammation and oxidants as evidence of systemic metabolic disease. It is our hypothesis that the specificity of detecting cardiovascular disease of metabolic causes will be greatly increased by a targeted proteomic approach to detect the effects of abnormal metabolism on proteins. This project takes advantage of our discoveries that multiple covalent oxidative and reactive lipid and glycation modifications occur on plasma proteins in patients with pulmonary hypertension or with systemic amyloid disease; these results serve as examples of how blood components can be "innocent passersby," modified in diseased tissue or in response to systemic metabolic changes. Our goal is to refine this approach by examining which proteins within the diseased heart and vasculature are modified and what modifications occur in response to metabolic disease, and then to identify a subset of these modified proteins in the plasma that show potential for use as tissue-specific biomarkers of the disease. To accomplish these tasks, we are continuing to develop and refine the proteomics pipeline and bioinformatics tools that we built over the last seven years in the Core Laboratory of the NIH/NHLBI-supported BUSM-Cardiovascular Proteomics Center. We are first quantifying changes in the abundances and modifications of heart and vascular tissue proteins in mouse models of human metabolic disease and then assess the occurrence of similar changes in the human population, in particular women and Blacks, which is at risk for or subject to heart failure as a consequence of metabolic disease. The expected results of the this research will be a set of markers of metabolic dysfunction that should serve as candidate early biomarkers for the development of cardiovascular dysfunction as a result of metabolic syndromes, as well as proven antibody and MS/MS methods for the detection and quantification of the key candidates. These should provide new and powerful approaches to the detection and monitoring of metabolic cardiovascular disease.