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Published on: August 29, 2018
Integrative Proteomic Analysis Reveals the Cytoskeleton Regulation and Mitophagy Difference Between Ischemic
Muyin Liu1, Linhui Zhai2, Zhaohua Yang3
1Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Insights
This study reveals distinct proteomic and phosphoproteomic differences in ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM). It identifies specific signaling pathways involved in each heart failure type, offering new therapeutic targets.
Area of Science:
- Cardiovascular Biology
- Proteomics and Phosphoproteomics
- Molecular Pathogenesis of Heart Failure
Background:
- Ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) are leading causes of end-stage heart failure.
- Limited understanding of global proteomic and phosphoproteomic dynamics hinders comprehension of their distinct biological characteristics and signaling pathways.
- Clarifying these differences is crucial for developing targeted therapies for heart failure.
Purpose of the Study:
- To comprehensively analyze the proteome and phosphoproteome in clinical heart tissues of ICM and DCM.
- To elucidate the distinct molecular mechanisms and signaling pathway activations underlying ICM and DCM.
- To identify potential therapeutic targets based on the identified molecular differences.
Main Methods:
- High-throughput quantitative proteomics and phosphoproteomics on clinical heart tissues (ICM, DCM, and normal controls).
- Integration of omics data with Western blots, phosphosite-specific mutation analysis, chemical intervention, and immunofluorescence validation.
- Analysis of signaling pathways including PRKACA-GSK3β in ICM and ROCK1-vimentin in DCM.
Main Results:
- Distinct protein and phosphorylation expression profiles clearly separated heart failure tissues (ICM and DCM) from normal controls.
- ICM showed significant activation of the PRKACA-GSK3β pathway, impacting microtubule and actin filament remodeling.
- DCM exhibited elevated mitochondrial energy supply injury, activating the ROCK1-vimentin pathway and promoting mitophagy.
Conclusions:
- This study delineates key distinguishing molecular features and mechanisms between ICM and DCM.
- Identified pathway activations (PRKACA-GSK3β in ICM, ROCK1-vimentin in DCM) highlight pathophysiologic heterogeneity.
- Provides a novel perspective and potential therapeutic targets for distinct types of heart failure.
Abstract:
Ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) are the two primary etiologies of end-stage heart failure. However, there remains a dearth of comprehensive understanding the global perspective and the dynamics of the proteome and phosphoproteome in ICM and DCM, which hinders the profound comprehension of pivotal biological characteristics as well as differences in signal transduction activation mechanisms between these two major types of heart failure. We conducted high-throughput quantification proteomics and phosphoproteomics analysis of clinical heart tissues with ICM or DCM, which provided us the system-wide molecular insights into pathogenesis of clinical heart failure in both ICM and DCM. Both protein and phosphorylation expression levels exhibit distinct separation between heart failure and normal control heart tissues, highlighting the prominent characteristics of ICM and DCM. By integrating with omics results, Western blots, phosphosite-specific mutation, chemical intervention, and immunofluorescence validation, we found a significant activation of the PRKACA-GSK3β signaling pathway in ICM. This signaling pathway influenced remolding of the microtubule network and regulated the critical actin filaments in cardiac construction. Additionally, DCM exhibited significantly elevated mitochondria energy supply injury compared to ICM, which induced the ROCK1-vimentin signaling pathway activation and promoted mitophagy. Our study not only delineated the major distinguishing features between ICM and DCM but also revealed the crucial discrepancy in the mechanisms between ICM and DCM. This study facilitates a more profound comprehension of pathophysiologic heterogeneity between ICM and DCM and provides a novel perspective to assist in the discovery of potential therapeutic targets for different types of heart failure.
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