Phosphoproteomic profiling of human myocardial tissues distinguishes ischemic from non-ischemic end stage heart failure

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 pr...

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Bibliographic Details
Published in:	PloS one Vol. 9; no. 8; p. e104157
Main Authors:	Schechter, Matthew A, Hsieh, Michael K H, Njoroge, Linda W, Thompson, J Will, Soderblom, Erik J, Feger, Bryan J, Troupes, Constantine D, Hershberger, Kathleen A, Ilkayeva, Olga R, Nagel, Whitney L, Landinez, Gina P, Shah, Kishan M, Burns, Virginia A, Santacruz, Lucia, Hirschey, Matthew D, Foster, Matthew W, Milano, Carmelo A, Moseley, M Arthur, Piacentino, 3rd, Valentino, Bowles, Dawn E
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 12-08-2014 Public Library of Science (PLoS)
Subjects:	Aged Alterations Apoptosis Biology and Life Sciences Cell adhesion Chaperones Chromatography Cluster Analysis Computational Biology Cytoskeleton Dehydrogenases Diagnosis, Differential Etiology Gene Expression Profiling Heart diseases Heart failure Heart Failure - diagnosis Heart Failure - etiology Heart Failure - metabolism Heart Ventricles - metabolism Humans Ischemia Kinases Liquid chromatography Male Mass spectrometry Mass spectroscopy Medicine and Health Sciences Metabolism Metabolome Metabolomics Middle Aged Molecular structure Myocardial Ischemia - complications Myocardium - metabolism Nutrition Peptides Phosphopeptides - metabolism Phosphoproteins - metabolism Phosphorylation Post-translation Protein Interaction Mapping Protein Interaction Maps Proteins Proteome Proteomics Proteomics - methods Reproducibility of Results Ribonucleic acid RNA RNA processing Signal transduction Signaling Structure-function relationships Surgery Tissues Titanium dioxide Transcription activation Ventricle North Carolina United States > US
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Competing Interests: The authors have declared no competing interests exist. Conceived and designed the experiments: JWT EJS VAB MDH MAM VP DEB. Performed the experiments: MAS MKHH LWN JWT EJS BJF CDT KAH ORI WLN GPL KMS MWF. Analyzed the data: MAS MKKH LWN JWT EJS BJF KMS LS MDH MWF VP DEB. Contributed reagents/materials/analysis tools: CAM VP. Contributed to the writing of the manuscript: MAS MKKH LWN JWT EJS BJF LS CAM DEB.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0104157