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Cardiac extracellular proteome profiling and membrane topology analysis using glycoproteomics.

ABSTRACT: Extracellular proteins are easily accessible, which presents a subproteome of molecular targets that have high diagnostic and therapeutic potential. Efforts have been made to catalog the cardiac extracellular matridome and analyze the topology of identified proteins for the design of therapeutic targets. Although many bioinformatics tools have been developed to predict protein topology, topology has been experimentally validated for only a very small portion of membrane proteins. The aim of this study was to use a glycoproteomics and MS approach to identify glycoproteins in the extracellular matridome of the infarcted left ventricle (LV) and provide experimental evidence for topological determination.Glycoproteomics analysis was performed on eight biological replicates of LV samples from wild-type mice at 7 days following myocardial infarction using SPE of glycopeptides, followed by mass spectrometric identification of N-linked glycosylation sites for topology assessment.We identified hundreds of glycoproteins, and the identified N-glycosylation sites provide novel information on the correct topology for membrane proteins present in the infarct setting.Our data provide the foundation for future studies of the LV infarct extracellular matridome, which may facilitate the discovery of drug targets and biomarkers.

SUBMITTER: Tian Y

PROVIDER: S-EPMC4212811 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Cardiac extracellular proteome profiling and membrane topology analysis using glycoproteomics.

Tian Yuan Y Koganti Tejaswi T Yao Zhihao Z Cannon Presley P Shah Punit P Pietrovito Laura L Modesti Alessandra A Aiyetan Paul P DeLeon-Pennell Kristine K Ma Yonggang Y Halade Ganesh V GV Hicks Chindo C Zhang Hui H Lindsey Merry L ML

Proteomics. Clinical applications 20140801 7-8

<h4>Purpose</h4>Extracellular proteins are easily accessible, which presents a subproteome of molecular targets that have high diagnostic and therapeutic potential. Efforts have been made to catalog the cardiac extracellular matridome and analyze the topology of identified proteins for the design of therapeutic targets. Although many bioinformatics tools have been developed to predict protein topology, topology has been experimentally validated for only a very small portion of membrane proteins. ...[more]

PMID: 24920555

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Project description:Heart failure (HF) is a worldwide pandemic with an unacceptable high level of morbidity and mortality. Understanding the different pathophysiological mechanisms will contribute to prevention and individualized therapy of HF. We established mouse models for ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) by inducing myocardial infarction (MI) and Coxsackievirus B3 infection, respectively. Isobaric tags for relative and absolute quantitation and liquid chromatography coupled with tandem mass spectrometry technology was used to identify the protein expression profiles in control and failing hearts. A total of 1,638 proteins were identified and compared in this proteomics analysis. Among them, 286 proteins were differently expressed. Gene ontology, KEGG pathway and ingenuity pathway analysis was performed to systematically assess the potential connections of the differentially expressed proteins to biological functions. Compared with control group, the differentially expressed proteins derived from the hearts of ICM and DCM mice were partially similar and mainly modulated in oxidative phosphorylation, metabolism and protein folding pathways. Moreover, difference still existed, the differentially expressed proteins between DCM and ICM hearts were significantly modulated in oxidative phosphorylation, metabolic and AMPK signaling pathways. Confirmatory western bolt analysis demonstrated that SDHB was down-regulated in both ICM and DCM hearts, while UQCRQ, GLUT4 and adiponectin were up-regulated in ICM hearts. Adenosine triphosphate (ATP) concentration significantly decreased in both DCM and ICM hearts. The protein expression of phospho-AMPK? decreased significantly in DCM hearts, but increased in ICM. In summary, oxidative phosphorylation, cardiac metabolism, and protein folding play critical roles in the pathogenesis of HF. The diverse changes in protein expression profiles between failing hearts induced by either MI or CVB3 infection demonstrated the heterogeneity of HF. Understanding the differences in proteome profiles could offer more precise therapeutic options for HF.

Dataset Information

Cardiac extracellular proteome profiling and membrane topology analysis using glycoproteomics.

Publications

Cardiac extracellular proteome profiling and membrane topology analysis using glycoproteomics.

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