2. Academic Validation
  3. Integrative proteomic analysis reveals the cytoskeleton regulation and mitophagy difference between ischemic cardiomyopathy and dilated cardiomyopathy

Integrative proteomic analysis reveals the cytoskeleton regulation and mitophagy difference between ischemic cardiomyopathy and dilated cardiomyopathy

  • Mol Cell Proteomics. 2023 Oct 16:100667. doi: 10.1016/j.mcpro.2023.100667.
Muyin Liu 1,  Linhui Zhai 2,  Zhaohua Yang 3,  Su Li 4,  Tianxian Liu 5,  Ao Chen 4,  Lulu Wang 6,  Youran Li 4,  Ruidong Li 7,  Chenguang Li 4,  Minjia Tan 8,  Zhangwei Chen 9,  Juying Qian 10
Affiliations

Affiliations

  • 1 Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 201203, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China; School of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China.
  • 3 Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 4 Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 201203, China.
  • 5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China.
  • 7 College of Pharmacy, Jiangsu Ocean University, Lianyungang, Jiangsu, 222000, China.
  • 8 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
  • 9 Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 201203, China. Electronic address: chen.zhangwei@zs-hospital.sh.cn.
  • 10 Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 201203, China. Electronic address: qian.juying@zs-hospital.sh.cn.
PMID: 37852321 DOI: 10.1016/j.mcpro.2023.100667
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 the PRKACA-GSK3β signaling pathway in ICM. This signaling pathway activation induced 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-VIM 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.

Keywords

Dilated cardiomyopathy; Ischemic heart disease; Pathophysiologic heterogeneity; Phosphoproteomics; Proteomics.

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