Protein kinetic signatures of the remodeling heart following isoproterenol stimulation.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Lam, MPY; Wang, D; Lau, E; Liem, DA; Kim, AK; Ng, DCM; Liang, X; Bleakley, BJ; Liu, C; Tabaraki, JD; Cadeiras, M; Wang, Y; Deng, MC; Ping, P

Published Date

  • April 2014

Published In

Volume / Issue

  • 124 / 4

Start / End Page

  • 1734 - 1744

PubMed ID

  • 24614109

Pubmed Central ID

  • PMC3973111

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

Digital Object Identifier (DOI)

  • 10.1172/JCI73787

Language

  • eng

Conference Location

  • United States