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Enhanced expression of the ubiquitin-proteasome system in the myocardium from patients with dilated cardiomyopathy referred for left ventriculoplasty: an immunohistochemical study with special reference to oxidative stress

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Abstract

The ubiquitin (Ub)-proteasome system (UPS) is an important proteolytic mechanism for selecting and digesting cytotoxic proteins. The aim of this study is to elucidate expression and in situ localization of the UPS in the myocardium from patients with dilated cardiomyopathy (DCM) with refractory heart failure. The expression profile of the oxidative stress-induced cytotoxic proteins was also examined. Myocardium was obtained from 26 patients with DCM at the left ventriculoplasty. Ten normal autopsied hearts served as controls. Myocardial expressions of Ub and proteasomes were studied immunohistochemically. Oxidative stresses were examined in point of localization of the oxidation-induced modifier molecules (OMM). The relationship between immunohistochemical results and clinical parameters was also evaluated. Both Ub and proteasomes were stained positive in granular structures accumulating between the myofibrils and adjacent to nuclei in cardiomyocytes. The OMMs were also positive in the same Ub-positive granular structures. The area fraction of Ub, proteasomes and OMM was significantly higher in DCM hearts than in normal controls. Significant positive correlation was observed between the area fractions of Ub and plasma levels of brain natriuretic peptide (p = 0.046) in DCM hearts. In conclusion, enhanced expression of the UPS colocalized with OMM in cardiomyocytes may be involved in the pathophysiology of DCM hearts.

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References

  1. Klausner RD, Sitia R (1990) Protein degradation in the endoplasmic reticulum. Cell 62:611–614

    Article  CAS  PubMed  Google Scholar 

  2. Hershko A, Ciechanover A, Varshavsky A (2000) Basic medical award. The ubiquitin system. Nat Med 6:1073–1081

    Article  CAS  PubMed  Google Scholar 

  3. Weissman AM (2001) Themes and variations on ubiquitylation. Nat Rev Mol Cell Biol 2:169–178

    Article  CAS  PubMed  Google Scholar 

  4. Ohsumi Y (2001) Molecular dissection of autophagy: two ubiquitin-like system. Nat Rev Mol Cell Biol 2:211–216

    Article  CAS  PubMed  Google Scholar 

  5. Wang CW, Klionsky DJ (2003) The molecular mechanism of autophagy. Mol Med 9:65–76

    PubMed  Google Scholar 

  6. Stadtman ER (1992) Protein oxidation and aging. Science 257:1220–1224

    Article  CAS  PubMed  Google Scholar 

  7. Bucciantini M, Giannoni E, Chiti F, Broni F, Formiqli L, Zurdo J, Taddei N, Ramponi G, Dobson CM, Stefani M (2002) Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416:483–484

    Article  Google Scholar 

  8. Belch JJ, Bridges AB, Scott N, Chopra M (1991) Oxygen free radicals and congestive heart failure. Br Heart J 65:245–248

    Article  CAS  PubMed  Google Scholar 

  9. Weekes J, Morrison K, Mullen A, Wait R, Barton P, Dunn MJ (2003) Hyperubiquitination of protein in dilated cardiomyopathy. Proteomics 3:208–216

    Article  CAS  PubMed  Google Scholar 

  10. Shimomura H, Terasaki F, Hayashi T, Kitaura Y, Isomura T, Suma T (2001) Autophagic degeneration as a possible mechanism of myocardial cell death in dilated cardiomyopathy. Jpn Circ J 65:965–968

    Article  CAS  PubMed  Google Scholar 

  11. Johnston JA, Ward CL, Kopito RR (1998) Aggresomes: a cellular response to misfolded proteins. J Cell Biol 143:1883–1898

    Article  CAS  PubMed  Google Scholar 

  12. Lowe J, Blanchard A, Morrell K, Lennox G, Revnolds L, Billett M, Landon M, Mayer RJ (1988) Ubiquitin is a common factor in intermediate filament inclusion bodies of diverse type in man, including those of Parkinson’s disease, Pick’s disease, and Alzheimer’s disease, as well as Rosenthal fibres in cerebellar astrocytomas, cytoplasmic bodies in muscle, and Mallory bodies in alcoholic liver disease. J Pathol 155:9–15

    Article  CAS  PubMed  Google Scholar 

  13. McNaught KS, Shashidharan P, Perl DP, Jenner P, Olanow CW (2002) Aggresome-related biogenesis of Lewy bodies. Eur J Neurosci 16:2136–2148

    Article  PubMed  Google Scholar 

  14. Kopito RR (2000) Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol 10:524–530

    Article  CAS  PubMed  Google Scholar 

  15. Tran PB, Miller RJ (1999) Aggregates in neurodegenerative disease: crows and power? Trends Neurosci 22:194–197

    Article  CAS  PubMed  Google Scholar 

  16. McMurray J, Chopra M, Abdullah I, Smith WE, Darqie HJ (1993) Evidence of oxidative stress in chronic heart failure in humans. Eur Heart J 14:1493–1498

    CAS  PubMed  Google Scholar 

  17. Keith M, Geranmayegan A, Sole MJ, Kurian R, Robinson A, Omran AS, Jeejeebhoy KN (1998) Increased oxidative stress in patients with congestive heart failure. J Am Coll Cardiol 31:1352–1356

    Article  CAS  PubMed  Google Scholar 

  18. Mallat Z, Philip I, Lebret M, Chatel D, Maclouf J, Tedqui A (1998) Elevated levels of 8-iso-prostaglandin F2α in pericardial fluid of patients with heart failure: a potential role for in vivo oxidant stress in ventricular dilatation and progression to heart failure. Circulation 97:1536–1539

    CAS  PubMed  Google Scholar 

  19. Okada K, Wangpoengtrakul C, Osawa T, Toyokuni S, Tanaka K, Uchida K (1999) 4-Hydroxy-2-nonenal-mediated impairment of intracellular proteolysis during oxidative stress. Identification of proteasomes as target molecules. J Biol Chem 274:23787–23793

    Article  CAS  PubMed  Google Scholar 

  20. Bulteau AL, Lundberg KC, Humphries KM, Sadek HA, Szweda PA, Friquet B, Szweda LI (2001) Oxidative modification and inactivation of the proteasome during coronary occlusion/reperfusion. J Biol Chem 276:30057–30063

    Article  CAS  PubMed  Google Scholar 

  21. McNaught KS, Mytilineou C, Jnobaptiste R, Yabut J, Shashidharan P, Jennert P, Olanow CW (2002) Impairment of the ubiquitin–proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures. J Neurochem 81:301–306

    Article  CAS  PubMed  Google Scholar 

  22. Majno G, Joris I (1995) Apoptosis, oncosis and necrosis. An overview of cell death. Am J Pathol 146:3–15

    CAS  PubMed  Google Scholar 

  23. Narula J, Haider N, Virmani R, DiSalvo TG, Kolodqie FD, Hajjar RJ, Schmidt U, Semigran MJ, Dec GW, Khaw BA (1996) Apoptosis in myocytes in end-stage heart failure. N Engl J Med 335:1182–1189

    Article  CAS  PubMed  Google Scholar 

  24. Mallat Z, Tedgui A, Fontaliran F, Frank R, Duriqon M, Fontaine G (1996) Evidence of apoptosis in arrhythmogenic right ventricular dysplasia. N Engl J Med 335:1190–1196

    Article  CAS  PubMed  Google Scholar 

  25. McDonald ER 3rd, El-Deiry WS (2004) Suppression of caspase-8- and -10-associated RING proteins results in sensitization to death ligands and inhibition of tumor cell growth. Proc Natl Acad Sci USA 101:6170–6175

    Article  CAS  PubMed  Google Scholar 

  26. Powell SR, Wang P, Divald A, Teichberg S, Haridas V, McCloskey TW, Davies KJA, Katzeff H (2005) Aggregates of oxidized proteins (lipofuscin) induce apoptosis through proteasome inhibition and dysregulation of proapoptotic proteins. Free Radic Biol Med 38:1093–1101

    Article  CAS  PubMed  Google Scholar 

  27. Tannous P, Zhu H, Nemchenko A, Berry JM, Johnstone JL, Shelton JM, Miller FJ Jr, Rothermel BA, Hill JA (2008) Intracellular protein aggregation is a proximal trigger of cardiomyocyte autophagy. Circulation 117:3070–3078

    Article  CAS  PubMed  Google Scholar 

  28. Jung T, Bader N, Grune T (2007) Lipofuscin. Formation, distribution, and metabolic consequences. Ann N Y Acad Sci 1119:97–111

    Article  CAS  PubMed  Google Scholar 

  29. Hasegawa K, Fujiwara H, Doyama K, Mukoyama M, Nakao K, Fujiwara T, Imura H, Kawai C (1993) Ventricular expression of atrial and brain natriuretic peptides in dilated cardiomyopathy. An immunohistochemical study of the endomyocardial biopsy specimens using specific monoclonal antibodies. Am J Pathol 142:107–116

    CAS  PubMed  Google Scholar 

  30. McDonagh TA, Robb SD, Murdoch DR, Morton JJ, Ford I, Morrison CE, Tunstall-Pedoe H, McMurray JJ, Dargie HJ (1998) Biochemical detection of left-ventricular systolic dysfunction. Lancet 351:9–13

    Article  CAS  PubMed  Google Scholar 

  31. Yamamoto K, Burnett JC Jr, Jougasaki M, Nishimura RA, Bailey KR, Saito Y, Nakao K, Redfield MM (1996) Superiority of brain natriuretic peptide as a hormonal maker of ventricular hypertrophy. Hypertension 28:988–994

    CAS  PubMed  Google Scholar 

  32. Tsutamoto T, Wada A, Maeda K, Hisanaga T, Maeda Y, Fukai D, Ohnishi M, Sugimoto Y, Kinoshita M (1997) Attenuation of compensation of endogenous cardiac natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. Circulation 96:509–516

    CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported in part by grants from the Ministry of Health, Labor and Welfare of Japan. The authors wish to express deep gratitude to Dr. Takafumi Ogawa and Mr. Masahiro Jo for their valuable technical assistance.

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Authors and Affiliations

  1. Department of Internal Medicine III, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, 569-8686, Japan

    Koji Otsuka, Fumio Terasaki, Hiroaki Shimomura, Bin Tsukada & Yasushi Kitaura

  2. First Department of Surgery, Kagawa University School of Medicine, Takamatsu, Japan

    Taiko Horii

  3. Department of Cardiovascular Surgery, Hayama Heart Center, Hayama, Japan

    Tadashi Isomura

  4. Department of Cardiovascular Surgery, The Cardiovascular Institute Hospital, Tokyo, Japan

    Hisayoshi Suma

  5. Department of Pathology, Osaka Medical College, Takatsuki, Japan

    Yuro Shibayama

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  1. Koji Otsuka
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  2. Fumio Terasaki
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  3. Hiroaki Shimomura
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  4. Bin Tsukada
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  9. Yasushi Kitaura
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Correspondence to Fumio Terasaki.

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Otsuka, K., Terasaki, F., Shimomura, H. et al. Enhanced expression of the ubiquitin-proteasome system in the myocardium from patients with dilated cardiomyopathy referred for left ventriculoplasty: an immunohistochemical study with special reference to oxidative stress. Heart Vessels 25, 474–484 (2010). https://doi.org/10.1007/s00380-010-0006-3

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  • DOI: https://doi.org/10.1007/s00380-010-0006-3

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