Protein kinetic signatures of the remodeling heart following isoproterenol stimulation

Protein temporal dynamics play a critical role in time-dimensional pathophysiological processes, including the gradual cardiac remodeling that occurs in early-stage heart failure. Methods for quantitative assessments of protein kinetics are lacking, and despite knowledge gained from single-protein s...

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Bibliographic Details
Published in:	The Journal of clinical investigation Vol. 124; no. 4; pp. 1734 - 1744
Main Authors:	Lam, Maggie P Y, Wang, Ding, Lau, Edward, Liem, David A, Kim, Allen K, Ng, Dominic C M, Liang, Xiangbo, Bleakley, Brian J, Liu, Chenguang, Tabaraki, Jason D, Cadeiras, Martin, Wang, Yibin, Deng, Mario C, Ping, Peipei
Format:	Journal Article
Language:	English
Published:	United States American Society for Clinical Investigation 01-04-2014
Subjects:	Adrenergic beta-Agonists - pharmacology Adult Animals Biomedical research Calcium Signaling Computational biology Deuterium Oxide Development and progression Disease Experiments Heart Heart - drug effects Heart failure Heart Failure - etiology Heart Failure - metabolism Homeostasis Humans Isoproterenol - pharmacology Isotopes Kinetics Male Mass Spectrometry Methods Mice Mice, Inbred ICR Mitochondria, Heart - metabolism Muscle Proteins - metabolism Myocardium - metabolism Peptides Physiological aspects Protein metabolism Protein synthesis Proteins Proteins - metabolism Technical Advance
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Summary:	Protein temporal dynamics play a critical role in time-dimensional pathophysiological processes, including the gradual cardiac remodeling that occurs in early-stage heart failure. Methods for quantitative assessments of protein kinetics are lacking, and despite knowledge gained from single-protein studies, integrative views of the coordinated behavior of multiple proteins in cardiac remodeling are scarce. Here, we developed a workflow that integrates deuterium oxide (2H2O) labeling, high-resolution mass spectrometry (MS), and custom computational methods to systematically interrogate in vivo protein turnover. Using this workflow, we characterized the in vivo turnover kinetics of 2,964 proteins in a mouse model of β-adrenergic-induced cardiac remodeling. The data provided a quantitative and longitudinal view of cardiac remodeling at the molecular level, revealing widespread kinetic regulations in calcium signaling, metabolism, proteostasis, and mitochondrial dynamics. We translated the workflow to human studies, creating a reference dataset of 496 plasma protein turnover rates from 4 healthy adults. The approach is applicable to short, minimal label enrichment and can be performed on as little as a single biopsy, thereby overcoming critical obstacles to clinical investigations. The protein turnover quantitation experiments and computational workflow described here should be widely applicable to large-scale biomolecular investigations of human disease mechanisms with a temporal perspective.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 Authorship note: Maggie P.Y. Lam, Ding Wang, Edward Lau, and David A. Liem contributed equally to this work.
ISSN:	0021-9738 1558-8238
DOI:	10.1172/jci73787