Phosphoproteomic profiling of human myocardial tissues distinguishes ischemic from non-ischemic end stage heart failure.
Abstract
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.
Type
Journal articleSubject
AgedCluster Analysis
Computational Biology
Diagnosis, Differential
Gene Expression Profiling
Heart Failure
Heart Ventricles
Humans
Male
Metabolome
Metabolomics
Middle Aged
Myocardial Ischemia
Myocardium
Phosphopeptides
Phosphoproteins
Protein Interaction Mapping
Protein Interaction Maps
Proteome
Proteomics
Reproducibility of Results
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https://hdl.handle.net/10161/13939Published Version (Please cite this version)
10.1371/journal.pone.0104157Publication Info
Schechter, Matthew A; Hsieh, Michael KH; Njoroge, Linda W; Thompson, J Will; Soderblom,
Erik J; Feger, Bryan J; ... Bowles, Dawn E (2014). Phosphoproteomic profiling of human myocardial tissues distinguishes ischemic from
non-ischemic end stage heart failure. PLoS One, 9(8). pp. e104157. 10.1371/journal.pone.0104157. Retrieved from https://hdl.handle.net/10161/13939.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Dawn Elizabeth Bowles
Assistant Professor in Surgery
Bryan Feger
Medical Writer, Sr
A scientist with basic and clinical research training, who is passionate about supporting
Duke investigators and strengthening research integrity.
Matthew Wolf Foster
Associate Professor in Medicine
Matthew Hirschey
Associate Professor of Medicine
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.
Olga Ilkayeva
Assistant Professor in Medicine
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
Carmelo Alessio Milano
Joseph W. and Dorothy W. Beard Distinguished Professor of Experimental Surgery
Martin Arthur Moseley III
Adjunct Professor in the Department of Cell Biology
Matthew Schechter
House Staff
Erik James Soderblom
Associate Research Professor of Cell Biology
Director, Proteomics and Metabolomics Core Facility
J. Will Thompson
Adjunct Assistant Professor in the Department of Pharmacology & Cancer Biology
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 Princi
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