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Integrated omics dissection of proteome dynamics during cardiac remodeling.

ABSTRACT: Transcript abundance and protein abundance show modest correlation in many biological models, but how this impacts disease signature discovery in omics experiments is rarely explored. Here we report an integrated omics approach, incorporating measurements of transcript abundance, protein abundance, and protein turnover to map the landscape of proteome remodeling in a mouse model of pathological cardiac hypertrophy. Analyzing the hypertrophy signatures that are reproducibly discovered from each omics data type across six genetic strains of mice, we find that the integration of transcript abundance, protein abundance, and protein turnover data leads to 75% gain in discovered disease gene candidates. Moreover, the inclusion of protein turnover measurements allows discovery of post-transcriptional regulations across diverse pathways, and implicates distinct disease proteins not found in steady-state transcript and protein abundance data. Our results suggest that multi-omics investigations of proteome dynamics provide important insights into disease pathogenesis in vivo.

SUBMITTER: Lau E

PROVIDER: S-EPMC5760723 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Integrated omics dissection of proteome dynamics during cardiac remodeling.

Lau Edward E Cao Quan Q Lam Maggie P Y MPY Wang Jie J Ng Dominic C M DCM Bleakley Brian J BJ Lee Jessica M JM Liem David A DA Wang Ding D Hermjakob Henning H Ping Peipei P

Nature communications 20180109 1

Transcript abundance and protein abundance show modest correlation in many biological models, but how this impacts disease signature discovery in omics experiments is rarely explored. Here we report an integrated omics approach, incorporating measurements of transcript abundance, protein abundance, and protein turnover to map the landscape of proteome remodeling in a mouse model of pathological cardiac hypertrophy. Analyzing the hypertrophy signatures that are reproducibly discovered from each o ...[more]

PMID: 29317621

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Project description:RationalePatients with and without cardiovascular diseases have been shown to be at risk of influenza-mediated cardiac complications. Recent clinical reports support the notion of a direct link between laboratory-confirmed influenza virus infections and adverse cardiac events.ObjectiveDefine the molecular mechanisms underlying influenza virus-induced cardiac pathogenesis after resolution of pulmonary infection and the role of necroptosis in this process.Methods and resultsHearts from wild-type and necroptosis-deficient (MLKL [mixed lineage kinase domain-like protein]-KO) mice were dissected 12 days after initial influenza A virus (IAV) infection when viral titers were undetectable in the lungs. Immunofluorescence microscopy and plaque assays showed presence of viable IAV particles in the myocardium without generation of interferon responses. Global proteome and phosphoproteome analyses using high-resolution accurate mass-based LC-MS/MS and label-free quantitation showed that the global proteome as well as the phosphoproteome profiles were significantly altered in IAV-infected mouse hearts in a strain-independent manner. Necroptosis-deficient mice had increased survival and reduced weight loss post-IAV infection, as well as increased antioxidant and mitochondrial function, indicating partial protection to IAV infection. These findings were confirmed in vitro by pretreatment of human and rat myocytes with antioxidants or necroptosis inhibitors, which blunted oxidative stress and mitochondrial damage after IAV infection.ConclusionsThis study provides the first evidence that the cardiac proteome and phosphoproteome are significantly altered post-pulmonary influenza infection. Moreover, viral particles can persist in the heart after lung clearance, altering mitochondrial function and promoting cell death without active replication and interferon responses. Finally, our findings show inhibition of necroptosis or prevention of mitochondrial damage as possible therapeutic interventions to reduce cardiac damage during influenza infections. Graphic Abstract: A graphic abstract is available for this article.

Dataset Information

Integrated omics dissection of proteome dynamics during cardiac remodeling.

Publications

Integrated omics dissection of proteome dynamics during cardiac remodeling.

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