Korean Circulation Journal

The Korean Society of Cardiology (대한심장학회)
권호 표지
DOI QR코드

DOI QR Code

Proteome-wide Characterization and Pathophysiology Correlation in Non-ischemic Cardiomyopathies

  • Seonhwa Lee (Division of Cardiology, Department of Internal Medicine, Cardiovascular Center, Keimyung University Dongsan Hospital, Keimyung University School of Medicine) ;
  • Dong-Gi Jang (Center for RNA Research, Institute for Basic Science) ;
  • Yeon Ju Kyoung (Center for RNA Research, Institute for Basic Science) ;
  • Jeesoo Kim (Center for RNA Research, Institute for Basic Science) ;
  • Eui-Soon Kim (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology) ;
  • Ilseon Hwang (Department of Pathology, Keimyung University Dongsan Hospital, Keimyung University School of Medicine) ;
  • Jong-Chan Youn (Division of Cardiology, Department of Internal Medicine, Seoul St. Mary's Hospital, Catholic Research Institute for Intractable Cardiovascular Disease, College of Medicine, The Catholic University of Korea) ;
  • Jong-Seo Kim (Center for RNA Research, Institute for Basic Science) ;
  • In-Cheol Kim (Division of Cardiology, Department of Internal Medicine, Cardiovascular Center, Keimyung University Dongsan Hospital, Keimyung University School of Medicine)
  • Received : 2024.01.23
  • Accepted : 2024.05.08
  • Published : 2024.08.01
Download PDF
⟨ Previous Next ⟩

Abstract

Background and Objectives: Although the clinical consequences of advanced heart failure (HF) may be similar across different etiologies of cardiomyopathies, their proteomic expression may show substantial differences in relation to underlying pathophysiology. We aimed to identify myocardial tissue-based proteomic characteristics and the underlying molecular pathophysiology in non-ischemic cardiomyopathy with different etiologies. Methods: Comparative extensive proteomic analysis of the myocardium was performed in nine patients with biopsy-proven non-ischemic cardiomyopathies (3 dilated cardiomyopathy [DCM], 2 hypertrophic cardiomyopathy [HCM], and 4 myocarditis) as well as five controls using tandem mass tags combined with liquid chromatography-mass spectrometry. Differential protein expression analysis, Gene Ontology (GO) analysis, and Ingenuity Pathway Analysis (IPA) were performed to identify proteomic differences and molecular mechanisms in each cardiomyopathy type compared to the control. Proteomic characteristics were further evaluated in accordance with clinical and pathological findings. Results: The principal component analysis score plot showed that the controls, DCM, and HCM clustered well. However, myocarditis samples exhibited scattered distribution. IPA revealed the downregulation of oxidative phosphorylation and upregulation of the sirtuin signaling pathway in both DCM and HCM. Various inflammatory pathways were upregulated in myocarditis with the downregulation of Rho GDP dissociation inhibitors. The molecular pathophysiology identified by extensive proteomic analysis represented the clinical and pathological properties of each cardiomyopathy with abundant proteomes. Conclusions: Different etiologies of non-ischemic cardiomyopathies in advanced HF exhibit distinct proteomic expression despite shared pathologic findings. The benefit of tailored management strategies considering the different proteomic expressions in non-ischemic advanced HF requires further investigation.

Keywords

Acknowledgement

This study was supported by the National Research Foundation of Korea (NRF-2020R1C1C1014161 to Kim IC, NRF-2021R1F1A1063430 to Youn JC), and Comparative Medicine Disease Research Center (NRF-2021R1A5A1033157 to Kim JS); by the grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI22C0198) to Kim IC; by the fund from the Korean Cardiac Research Foundation (202202-01) and by the Research Fund of Seoul St. Mary's Hospital, Catholic University of Korea (2022) to Youn JC. Kim JS thanks the Institute for Basic Science (IBS-R008-D1), funded by the Ministry of Science and ICT of Korea, for support.

References

  1. Greenberg B. Medical management of patients with heart failure and reduced ejection fraction. Korean Circ J 2022;52:173-97.
  2. Dunlay SM, Roger VL, Killian JM, et al. Advanced heart failure epidemiology and outcomes: a population-based study. JACC Heart Fail 2021;9:722-32.
  3. Choi HM, Park MS, Youn JC. Update on heart failure management and future directions. Korean J Intern Med 2019;34:11-43.
  4. Cooper LT Jr. Myocarditis. N Engl J Med 2009;360:1526-38.
  5. Olivotto I, Oreziak A, Barriales-Villa R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2020;396:759-69.
  6. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med 2018;379:1007-16.
  7. Cao TH, Jones DJ, Voors AA, et al. Plasma proteomic approach in patients with heart failure: insights into pathogenesis of disease progression and potential novel treatment targets. Eur J Heart Fail 2020;22:70-80.
  8. Aye TT, Scholten A, Taouatas N, et al. Proteome-wide protein concentrations in the human heart. Mol Biosyst 2010;6:1917-27.
  9. Colak D, Alaiya AA, Kaya N, et al. Integrated left ventricular global transcriptome and proteome profiling in human end-stage dilated cardiomyopathy. PLoS One 2016;11:e0162669.
  10. Li W, Rong R, Zhao S, et al. Proteomic analysis of metabolic, cytoskeletal and stress response proteins in human heart failure. J Cell Mol Med 2012;16:59-71.
  11. Lee JH, Lee SE, Cho MC. Clinical Implication of Genetic Testing in Dilated Cardiomyopathy. Int J Heart Fail 2021;4:1-11.
  12. Rueda F, Borras E, Garcia-Garcia C, et al. Protein-based cardiogenic shock patient classifier. Eur Heart J 2019;40:2684-94.
  13. Cao TH, Jones DJ, Quinn PA, et al. Using matrix assisted laser desorption ionisation mass spectrometry (MALDI-MS) profiling in order to predict clinical outcomes of patients with heart failure. Clin Proteomics 2018;15:35.
  14. Garmany R, Bos JM, Tester DJ, et al. Multi-Omic architecture of obstructive hypertrophic cardiomyopathy. Circ Genom Precis Med 2023;16:e003756.
  15. Ketema EB, Lopaschuk GD. Post-translational acetylation control of cardiac energy metabolism. Front Cardiovasc Med 2021;8:723996.
  16. Antozzi C, Zeviani M. Cardiomyopathies in disorders of oxidative metabolism. Cardiovasc Res 1997;35:184-99.
  17. Zhang X, Ji R, Liao X, et al. MicroRNA-195 regulates metabolism in failing myocardium via alterations in sirtuin 3 expression and mitochondrial protein acetylation. Circulation 2018;137:2052-67.
  18. Peugnet V, Chwastyniak M, Mulder P, et al. Mitochondrial-targeted therapies require mitophagy to prevent oxidative stress induced by SOD2 inactivation in hypertrophied cardiomyocytes. Antioxidants 2022;11:723.
  19. Schaper J, Froede R, Hein S, et al. Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy. Circulation 1991;83:504-14.
  20. Kalsi KK, Smolenski RT, Pritchard RD, Khaghani A, Seymour AM, Yacoub MH. Energetics and function of the failing human heart with dilated or hypertrophic cardiomyopathy. Eur J Clin Invest 1999;29:469-77.
  21. Matsushima S, Sadoshima J. The role of sirtuins in cardiac disease. Am J Physiol Heart Circ Physiol 2015;309:H1375-89.
  22. Tanno M, Kuno A, Yano T, et al. Induction of manganese superoxide dismutase by nuclear translocation and activation of SIRT1 promotes cell survival in chronic heart failure. J Biol Chem 2010;285:8375-82.
  23. Alcendor RR, Gao S, Zhai P, et al. Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ Res 2007;100:1512-21.
  24. Liu Y, Afzal J, Vakrou S, et al. Differences in microRNA-29 and pro-fibrotic gene expression in mouse and human hypertrophic cardiomyopathy. Front Cardiovasc Med 2019;6:170.
  25. Cannon MV, van Gilst WH, de Boer RA. Emerging role of liver X receptors in cardiac pathophysiology and heart failure. Basic Res Cardiol 2016;111:3.
  26. Lu H, Sun J, Hamblin MH, Chen YE, Fan Y. Transcription factor EB regulates cardiovascular homeostasis. EBioMedicine 2021;63:103207.
  27. Sardiello M, Palmieri M, di Ronza A, et al. A gene network regulating lysosomal biogenesis and function. Science 2009;325:473-7.
  28. Kanamori H, Yoshida A, Naruse G, et al. Impact of autophagy on prognosis of patients with dilated cardiomyopathy. J Am Coll Cardiol 2022;79:789-801.
  29. Heymans S, Eriksson U, Lehtonen J, Cooper LT Jr. The quest for new approaches in myocarditis and inflammatory cardiomyopathy. J Am Coll Cardiol 2016;68:2348-64.
  30. Melacini P, Basso C, Angelini A, et al. Clinicopathological profiles of progressive heart failure in hypertrophic cardiomyopathy. Eur Heart J 2010;31:2111-23.