Phosphoproteomic profiling of human myocardial tissues distinguishes ischemic from non-ischemic end stage heart failure.
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2014
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The molecular differences between ischemic (IF) and non-ischemic (NIF) heart failure are poorly defined. A better understanding of the molecular differences between these two heart failure etiologies may lead to the development of more effective heart failure therapeutics. In this study extensive proteomic and phosphoproteomic profiles of myocardial tissue from patients diagnosed with IF or NIF were assembled and compared. Proteins extracted from left ventricular sections were proteolyzed and phosphopeptides were enriched using titanium dioxide resin. Gel- and label-free nanoscale capillary liquid chromatography coupled to high resolution accuracy mass tandem mass spectrometry allowed for the quantification of 4,436 peptides (corresponding to 450 proteins) and 823 phosphopeptides (corresponding to 400 proteins) from the unenriched and phospho-enriched fractions, respectively. Protein abundance did not distinguish NIF from IF. In contrast, 37 peptides (corresponding to 26 proteins) exhibited a ≥ 2-fold alteration in phosphorylation state (p<0.05) when comparing IF and NIF. The degree of protein phosphorylation at these 37 sites was specifically dependent upon the heart failure etiology examined. Proteins exhibiting phosphorylation alterations were grouped into functional categories: transcriptional activation/RNA processing; cytoskeleton structure/function; molecular chaperones; cell adhesion/signaling; apoptosis; and energetic/metabolism. Phosphoproteomic analysis demonstrated profound post-translational differences in proteins that are involved in multiple cellular processes between different heart failure phenotypes. Understanding the roles these phosphorylation alterations play in the development of NIF and IF has the potential to generate etiology-specific heart failure therapeutics, which could be more effective than current therapeutics in addressing the growing concern of heart failure.
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Schechter, Matthew A, Michael KH Hsieh, Linda W Njoroge, J Will Thompson, Erik J Soderblom, Bryan J Feger, Constantine D Troupes, Kathleen A Hershberger, et al. (2014). Phosphoproteomic profiling of human myocardial tissues distinguishes ischemic from non-ischemic end stage heart failure. PLoS One, 9(8). p. e104157. 10.1371/journal.pone.0104157 Retrieved from https://hdl.handle.net/10161/13939.
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J. Will Thompson
Dr. Thompson's research focuses on the development and deployment of proteomics and metabolomics mass spectrometry techniques for the analysis of biological systems. He served as the Assistant Director of the Proteomics and Metabolomics Shared Resource in the Duke School of Medicine from 2007-2021. He currently maintains collaborations in metabolomics and proteomics research at Duke, and develops new tools for chemical analysis as a Principal Scientist at 908 Devices in Carrboro, NC.
Erik James Soderblom
Director, Proteomics and Metabolomics Core Facility
Bryan Feger
A scientist with basic and clinical research training, who is passionate about supporting Duke investigators and strengthening research integrity.
Olga Ilkayeva
Olga Ilkayeva, Ph.D., is the Director of the Metabolomics Core Laboratory at Duke Molecular Physiology Institute. She received her Ph.D. training in Cell Regulation from UT Southwestern Medical Center at Dallas, TX. Her postdoctoral research in the laboratory of Dr. Chris Newgard at Duke University Medical Center focused on lipid metabolism and regulation of insulin secretion. As a research scientist at the Stedman Nutrition and Metabolism Center, Dr. Ilkayeva expanded her studies to include the development of targeted mass spectrometry analyses. Currently, she works on developing and validating quantitative mass spectrometry methods used for metabolic profiling of various biological models with emphasis on diabetes, obesity, cardiovascular disease, and the role of gut microbiome in both health and disease.
Matthew Hirschey
The Hirschey Lab in the Duke Molecular Physiology Institute, and the Departments of Medicine and Pharmacology & Cancer Biology at Duke University studies different aspects of metabolic control, mitochondrial signaling, and cellular processes regulating human health and disease.
Matthew Wolf Foster
Carmelo Alessio Milano
Dawn Elizabeth Bowles
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