Cardiac Proteome Profiling in Ischemic and Dilated Cardiomyopathy Mouse Models

Danbo Lu,Yunzeng Zou,Jianguo Jia,Yan Xia,Junbo Ge,Yuan Wu,Zhangwei Chen,Aijun Sun,Juying Qian,Ao Chen

doi:10.3389/fphys.2019.00750

Abstract

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-AMPKα 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.

Highlights

Heart failure (HF) is a worldwide pandemic with an unacceptable high level of morbidity and mortality and results in an enormous medical and socio-economic burden (Benjamin et al, 2018)
Compared to mice in the control group, mice injected with Coxsackievirus B3 (CVB3) had significantly elevated left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) while Left ventricular ejection fraction (LVEF) was significantly decreased (P < 0.05) (Figures 1B–D)
We further identified the different pathophysiological changes that arose in Dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) hearts

Summary

Introduction

Heart failure (HF) is a worldwide pandemic with an unacceptable high level of morbidity and mortality and results in an enormous medical and socio-economic burden (Benjamin et al, 2018). Coxsackievirus B3 (CVB3) is the dominant etiological agent that induces acute and chronic viral myocarditis (Bowles et al, 2005; Esfandiarei and McManus, 2008; Weintraub et al, 2017). Both direct virus- and immune-mediated injuries contribute to the development of myocarditis and to DCM. CVB3 induced experimental murine models for HF have been widely used to investigate the molecular pathology of DCM (Esfandiarei and McManus, 2008). ICM results in more than 60% of all patients developing systolic congestive heart failure. Myocardial infarction (MI) and subsequent post-infarct remodeling are major etiologies of ICM (Sutton and Sharpe, 2000)

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Results

Conclusion